radiopharmaceuticals: an insight into the latest advances

Review

Radiopharmaceuticals: An insight into the latest advancesin medical uses and regulatory perspectives

DEEPAK KAUSHIK1, POOJA JANGRA1, RAVINDER VERMA

1,DEEPIKA PUROHIT2, PARIJAT PANDEY3, SANDEEP SHARMA

4 andRAKESH KUMAR SHARMA

5*1Department of Pharmaceutical Sciences, Maharshi Dayanand University,

Rohtak 124 001, India2Department of Pharmaceutical Sciences, Indira Gandhi University, Meerpur,

Rewari 123 401, India3Shri Baba Mastnath Institute of Pharmaceutical Sciences and Research, Baba Mastnath University,

Rohtak 124 001, India4I.K. Gujral Punjab Technical University, Jalandhar 144 603, India

5Saveetha Institute of Medical and Technical Sciences, 162, Poonamallee High Road,Chennai 600 077, India

*Corresponding author (Email, [email protected])

MS received 5 August 2020; accepted 25 January 2021

The growing armamentarium of potential radioisotopes and increased demand for radiopharmaceuticals (RPs)have catapulted their biomedical applications on a trajectory of higher growth in the modern healthcareestablishment. Nuclear medicine technology is now regarded as an essential tool for diagnosis, palliation,therapy, and theranostic applications. The associated radiation safety issues need to be emphasized in the formof adequate regulatory action to warrant their safe and effective use. The RPs attracts considerable attentionfrom both pharmaceutical and nuclear regulators due to their constituent pharmaceutical and radioactivecomponents. So, a critical examination of applications of RPs, the latest advances in their development, and theexisting regulatory guidelines for RPs have been carried out. This review presents a brief overview of RPs andrecent studies on their diagnostic, therapeutic, and theranostic applications. Comprehensive comparativeinformation on regulatory perspectives of RPs in major pharmaceutical jurisdictions such as the United States(US), the European Union (EU), and India reveals ambiguities and heterogeneity. The present studies discussthe importance of RPs in the current healthcare domain, their recent applications, and strive to intensify theconcern for an ambient and harmonized regulatory setup.

Keywords. Diagnostic radiopharmaceuticals; gamma and positron emission tomography; radiopharmaceu-ticals; regulation; theranostic radiopharmaceuticals; therapeutic radiopharmaceuticals

1. Introduction

Radiopharmaceuticals (RPs) is a special class of phar-maceutical formulations in which a radioisotope attachedto a pharmaceutical moiety, is delivered by inhalation,oral, intravenous, or interstitial route for diagnostic and/or

therapeutic purposes. It is usually composed of either astandalone radionuclide or a radioisotope bonded to anorganic molecule (Alsharef et al. 2020). The organicmolecule act as a carrier of the radioisotope to specificorgans, tissues, or cells. The radioisotope is selectedbased on the type of radiation emitted by it. For diagnostic

http://www.ias.ac.in/jbiosci

J Biosci (2021) 46:27 � Indian Academy of SciencesDOI: 10.1007/s12038-021-00147-5 (0123456789().,-volV)(0123456789().,-volV)

purposes, the radioisotopes emitting gamma rays directlyor emitting very high energy photons indirectly as a resultof the reaction of a positronwith an electron in the vicinity(a process termed as annihilation), are selected; while fortherapeutic use, the radioisotopes emitting a- or ß-parti-cles are carefully chosen for the destruction of localiseddiseased body cells (Farzin et al. 2019). Usually,radioisotopes for imaging purposes include Iodine-123 (123I), Technetium-99m (99mTc), Thallium-201 (201-

Tl), Indium-111 (111In) and Fluorine-18 (18F). Thecommonly used radioisotopes employed for therapeuticpurposes are 131I, Rhenium-188 (188Rh), Yttrium-90 (90-

Y), Phosphorus-32 (32P), and Lutetium-177 (177Lu). Theresidence timeof these radioisotopes in thehumanbody asdetermined by their half-lives is longer than those used fordiagnostic use. They are often used for palliation in bonecancer, arthritis and destruction of cancer cells etc. Thecurrent trend of RPs is the development of new innovativeclinically important moieties both from specialised ther-anostic and personalized medicine point of view.With the advent of innovative RPs and novel imag-

ing techniques, the diagnosis of various diseased con-ditions including the study of the functional status ofvarious organs/systems can be easily and effectivelycarried out. The global market of RPs is growingcontinuously and is expected to reach USD 5.2 billionby 2024 from an estimated USD 4.1 billion in 2019,growing at a CAGR of 4.7%. The diagnostic radio-pharmaceuticals market accounted for the largest shareof the nuclear medicine market (https://www.marketsandmarkets.com/Market-Reports//radiopharmaceuticals-market-417.html?gclid=Cj0KCQjwl4v4BRDaARIsAFjATPmElMetCyt4v1vw0I16dhx195fHyLNjVvpDX5jiH_l_otfBzZaihgaAhFZEALw_wcB). The rising preva-lence of cancer and cardiovascular diseases, increasinguse of single-photon emission computerised tomography(SPECT) and positron emission tomography (PET)imaging, and advancements in radiotracers are the maindrivers of the growth of this segment. The high demandfor RPs in the world market can be attributed to the higheffectiveness of the radionuclides and universal cytotoxicproperties of therapeutic RPs in destroying cancerouscells through ionising radiation (Puttemans et al. 2019).Some of the commonly used commercial RPs along withtheir intended applications are given in table 1

1.1 Challenges for RPs

The development of RP is a very challenging field dueto the following facts (Ramamoorthy 2018; Vermeulenet al. 2019):

• Designing and developing specific and efficaciousRPs requires careful selection of an appropriatevector (carrier) and a suitable radionuclide to offereffective options in radiodiagnosis and radiothera-peutics or theranostics.

• Radiation exposure may result in adverse eventsranging from skin and tissue rashes to more life-threatening conditions.

• The selection of the dose needs careful consider-ation especially in transforming the dose of radio-pharmaceutical formulation for the diagnosispurpose into therapeutic purpose. The adjustmentof adult dose of RPs in children is anotherchallenge that needs to be tackled to check thelikely hazards caused by radiation exposure inchildren.

• The harmonisation of guidelines for all the aspectsrelated to RPs is another area that needs utmostattention as the inconsistencies in the guidelinesand the regulations make it very difficult to produceand approve these products. All the stakeholdersincluding the regulatory bodies, radiopharmaceuti-cal manufacturing units, nuclear medicine estab-lishments, and National and Internationalinstitutions such as Atomic Energy RegulatoryBoard (AERB), International Atomic EnergyAgency (IAEA), Nuclear Energy Agency- Organ-isation for Economic Co-operation and Develop-ment (NEA-OECD), and World HealthOrganisation (WHO) could play an arduous rolein this direction.

• There are regulatory hurdles involved in the clinicaltrial process of RPs. This is significant for thesuccessful commercial launch of the new RPsespecially in the studies involving normal healthyvolunteers and the studies involving radiationexposure.

2. Application of RPs

RPs offers multifarious applications that can be broadlyclassified into three major areas as follows:

2.1 Diagnostic applications

RPs can be utilised to obtain diagnostic information forseveral diseases by the measurement of radioactivitydistribution in the human body under normal andpathological conditions. Gamma Camera, SPECT, andPET are some of the important imaging techniques

27 of 25 Deepak Kaushik et al.

being employed currently for the diagnosis of diseasesusing RPs (Pascu and Dilworth 2014). The RPsemployed in these techniques are short-lived radionu-clides generally bound to organic compounds. Themost commonly used radionuclides in diagnosticapplications along with their important physical prop-erties are given in table 2. The diagnostic informationis revealed by detecting the radioactivity accumulatedin the particular organ for which the study is beingcarried out (Keresztes et al. 2015). The RPs are gen-erally administered by oral, intravenous, and inhalation

routes to study the functioning of various organs suchas lungs, heart, kidney, brain, blood circulation, andbone metabolism (Drozdovitch et al. 2015; Payollaet al. 2019). Laudicella et al. described the latest state-of-the-art advancements of nuclear medicine forimaging melanoma (Laudicella et al. 2020). The use of18F-fluorodeoxyglucose (FDG) PET/computed tomog-raphy (CT) and its latest innovations in the detection ofmalignant melanoma was adequately described. Thedigital PET detector technology in PET/CT andPET/magnetic resonance imaging (MRI) was reported

Table 1. Commercial radiopharmaceutical products for use in Nuclear Medicine

Radiopharmaceuticalproduct Trade name Manufacturer Applications

68G-dotatate NETSPOTTM Advanced Accelerator Applications,SA20 Rue Diesel01630 Saint-Genis-PouillyFrance

For the imaging of neuroendocrine tumours(NETs) in adult and pediatric patients

99mTc-sestamibi Cardiolite� Lantheus Medical Imaging331 Treble Cove Rd.N. Billerica, MA 01862

For imaging of coronary artery disease

9mTc-tetrofosmin MyoviewTM GE Healthcare, 3000 N GrandviewBlvd, Waukesha, WI 53188, UnitedStates

For imaging of coronary artery disease bylocalizing myocardial ischemia

90Y-ibritumomabtiuxetan

Zevalin� Acrotech Biopharma 279 PrincetonHightstown Rd., East Windsor, NJ08520

For the treatment of non-Hodgkin’slymphoma (NHL)

18F-flucicovine AxuminTM Blue Earth Diagnostics MagdalenCentreThe Oxford Science ParkOxford, GB

For PET imaging in men with suspectedprostate cancer

131I-LipiodolInjection

IOM 40� Board of Radiation and IsotopeTechnology V.N. Purav Marg,Mumbai-400 094

For the treatment of hepatocellular carcinoma

[177Lu] Lutetium LUM-1� Board of Radiation and IsotopeTechnology V.N. Purav Marg,Mumbai-400 094

For the metastatic bone pain palliation

131I-iobenguane AZEDRA� Progenics� Pharmaceuticals OneWorld Trade Center, 47th Floor,Suite J, New York, NY 10007

For the treatment of metastaticpheochromocytoma or paraganglioma

125I-iothalamate Glofil-125� IsoTex Diagnostics 1511 County Rd129, Pearland, TX 77511

For renal function imaging

99mTc-mertiatide MAG3� Landauer RPs Pvt. Ltd.NSW 2150Australia

As a renal imaging agent for the use in thediagnosis of congenital and acquiredabnormalities, renal failure, urinary tractobstruction

68Ga-PSMA-11 TLX591-CDx�

Telix Pharmaceuticals Ltd., Suite401 55 Flemington Road, NorthMelbourne, VICAustralia, 3051

It is used as an imaging radiopharmaceuticalfor the imaging of metastatic prostate cancer

18F-flutemetamol VizamylTM GE Healthcare, 3000 N GrandviewBlvd, Waukesha, WI 53188, UnitedStates

Indicated for PET imaging of the brain forevaluation of Alzheimer’s disease (AD)

Radiopharmaceuticals of 25 27

to be highly useful in the detection of very smalllesions and positively impacting the outcome of thediseases (Laudicella et al. 2020).Fang and Liu reviewed the role of 99mTc Radiotracers

such as 99mTc-3SPboroxime, 99mTc-Tetrofosmin, and99mTc-Sestamibi for myocardial perfusion imaging bySPECT. Among the various radiotracers, 99mTc-3SPboroximine was found to be excellent in detectingperfusion defects and determination of regional bloodflow rate. The development of these radiotracers canprove to be of great help in the diagnosis of coronaryartery diseases and assessment of the risk of a heart attackin cardiac patients (Fang and Liu 2019).PET/CT was utilized by Zhang et al. in the diagnosis

of prosthetic joint infections (Zhang et al. 2016). Theinvestigation was based on the fact that phosphoryla-tion of Fialuridine (FIAU), a nucleoside analog bybacterial thymidine kinase resulted in the trapping of[124I]-FIAU within the bacteria which can be detectedby PET/CT. It was reported that suspected patients withprosthetic joint infections (PJI) very well tolerated[124I]-FIAU and had acceptable dosimetry. However,the poor image quality and low-specificity were majorlimitations reported in this study (Zhang et al. 2016).Fan et al. combined Pyro pheophorbide-a pyropheophorbide a (Pyro), RGD dimer peptide, and Cop-per-64 (64Cu) to design and synthesize a novel mole-cule 64Cu-Pyro-3PRGD2 (Fan et al. 2020). Thedeveloped molecule showed high potential as amolecular imaging probe for the diagnosis of thetumour (Fan et al. 2020). Sager et al. reviewed the

application of 2-deoxy-2-[18fluorine] fluoro-D-glucosePET (18F-FDG PET) for the diagnosis of small-celllung cancer.[15] This established that PET is an effec-tive tool for non-invasive molecular imaging and canbe exploited for the management of patients withsmall-cell lung cancer (Sager et al. 2019).Kostenikov et al. demonstrated the utility of

Rubidium-82 (82Rb) -chloride in the successful diag-nosis of brain tumour and non-neoplastic abnormalmasses (Kostenikov et al. 2019). The study was carriedout on a total of 21 patients, out of which 14 patientswere diagnosed with brain tumours. In 14 patientsdiagnosed with a brain tumour, 10 were diagnosed withmalignant tumour during PET study with 82Rb-chlo-ride. The high uptake of radiopharmaceutical wasdetected in the image of a tumour node as shown infigure 1. The results of the study indicated the suc-cessful use of 82Rb-chloride in the detection ofmalignant tumours owing to its high uptake in amalignant tumour, ultra-short half-life, and low absor-bed radiation dose (Kostenikov et al. 2019).Carollo et al. reviewed RPs used in imaging pan-

creatic neuroendocrine tumours (Carollo et al. 2019).The gallium-68 [68Ga]-1,4,7,10-tetra-azacyclodode-cane-N, N0, N00, N000-tetra-acetic acid (DOTA)-somato-statin analogs, [18F]-fluorodopa and [18F]-FDGradioisotopes were clinically being explored for thisinvestigation (Carollo et al. 2019).The study conducted by Shi et al. indicated the role

of [68Ga] Ga-HBED-CC-DiAsp (Di-Aspartic acidderivative of N, N0-bis [2-hydroxy-5-(carboxyethyl)

Table 2. Radionuclides in diagnostic applications along with their important physical properties

S.No Radionuclide t1/2/Emission Diagnostic application

1. K-42 12.36 h/Beta particles In diagnosis of brain tumour and assessment of potassium distribution inbody fluids

2. Ga-77 3.3 days/Gamma rays For tumour imaging by SPECT and study of acute inflammatory lesions3. Co-57 271.79 days/Gamma Rays For the diagnosis of anemia and intestinal absorption4. Se-75 119.779 days/Gamma rays For liver diagnosis and assessment of enterohepatic circulation of bile salts5. Cu-64 12.7 h/Beta particles For the diagnosis of tumour6. Tc-99m 6 h/Gamma rays For the diagnosis of coronary artery diseases, cancerous lesions,

metastasis and kidney/thyroid/liver function test7 Rb-82 76.4s/Beta particles In neurooncology for the diagnosis of malignant tumours8. F-18 110 m/Beta particles To study brain functions in tumours, dementia, epilepsy and also in

diagnosis of heart functions9. Tl-201 72.912 h/Gamma rays In stress tests for risk stratification of patients with coronary artery disease

10. In-111 2.8047 days/Gamma rays Used as complex for developing antibody-based radio immunodiagnostics10. I-124 4.18 days/Beta particles For the diagnosis of prosthetic joint infection11. Ga-68 67.629 min/Beta particles For the imaging of metastatic prostate cancer


benzyl]-ethylenediamine-N, N0-diacetic acid) as a PETimaging agent for the assessment of renal functions. Intheir study, it was revealed that [68Ga] Ga-HBED-CC-Di Asp can be easily prepared at room temperature andpromising results were obtained in the in vitro andin vivo biodistribution studies (Shi et al. 2020).The use of RPs in cardiac diagnosis was studied by

Ilyushenkova et al. who investigated the role of

inflammatory processes in the myocardium of patientswith atrial fibrillation (Ilyushenkova et al. 2020). Theaccumulation of 99mTc-Pyrophosphate in the myo-cardium was quantitatively assessed using SPECT/CT.A very high-sensitivity, accuracy, and specificity indiagnosing myocarditis was reported. Figure 2 showsthe SPECT image combined with multi-slice CTangiography based on 99mTc-Pyrophosphate. The

Figure 1. Female patient (A) at MRI (T2-weighted image), the tumour is well visible, and perifocal edema is defined.(B) 18F-FDG PET image demonstrates heterogeneous unsharp mass with the high glycolytic rate glycolysis (UI = 1.0). Thelesion is partially visible due to its location in the white matter as well as to edema and is chemization of the adjacent braincortex. (C) 82Rb-chloride PET image demonstrates a sharp homogeneous hypervascular focus with high radiopharmaceuticaluptake in the tissue phase (UI = 17) (position 1). Contralateral brain cortex is shown in position 2. (D) Activity/Time curveof the lesion (1) shows that the tumour has the high vascularization degree (VD = 2.1). Vascular permeability is impaired.Within the tissue phase, high radiopharmaceutical uptake in tumour exceeds the radiopharmaceutical uptake in thecontralateral brain cortex (2) in 17 times. A typical for malignant tumours slow monotonic radiopharmaceutical uptake in thetumour within the tissue phase is observed. Reproduced from Kostenikov et al. (2019) under creative commons CC BYlicense � 2019 Institution for Nuclear Research of Russian Academy of Science (INR RAS) Brain and Behavior Publishedby Wiley Periodicals, Inc.


arrows shown in the image are indicative of the accu-mulation of radiopharmaceutical in the middle septalpart of the left ventricle and low-intensity accumulationin the anterolateral region of the left ventricle (Ilyush-enkova et al. 2020).Annexin A1 has demonstrated complex roles in

many diverse cellular functions, such as membraneinteractions, inflammation, phagocytosis, regulation ofproliferation, and cell apoptosis (Sugimoto et al. 2016).Annexin A1 is also involved in carcinogenesis and/ortumour progression by participating in cell proliferationand differentiation, cell signaling, and metastasis indi-cating its role as a potential biomarker for solid tumourimaging and screening (Biaoxue et al. 2014). Chenrecently evaluated the targeting effect of a radiolabeledpeptide 18F-Al-NODA-Bn-p-SCN-GGGRDN-IF7 inthe Anxa1 positive A431 tumour model (Chen 2019).The radiolabeled peptide was prepared by labeling thepeptide NODA-Bn-p-SCN-GGGRDN-IF7 withradionuclide Al18F. The study demonstrated the Anxa 1binding specificity indicating the potential of 18F-Al-NODA-Bn-p-SCN-GGGRDN-IF7 in detecting Anxa 1level in cancers (Chen 2019). The authors alsoexplored the role of another radiolabeled peptide99mTc-p-SCN-Bn-DTPA-GGGRDN-IF7 (Tc-RIF7) as apotential target probe for detecting Anxa1 levels incancers. The study conducted on Uranium-87 (87U)tumour mode clearly showed the targeting character-istics of Anxa 1 by clear visualization of tumours inSPECT imaging (Chen et al. 2020).Shamsel-Din et al. demonstrated the utility of the

99mTc-diester complex as a solid tumour imaging agent(Shamsel-Din et al. 2020). The biodistribution studydemonstrated a high target to a non-target ratio intumour-bearing mice and the diester complex showed a

high percent of inhibition when evaluated against thebreast cancer cell lines (MCF-7) (Shamsel-Din et al.2020).

2.2 Therapeutic applications

Several RPs are currently being used for therapeuticapplications for both curative and palliative treatmentby absorption and subsequent destruction of diseasedcells (Ercan and Caglar 2000). The radionuclide withhigh linear energy such as a- and ß- particles are usedin internal radiotherapy for the treatment of malignantcells and micro-metastases. The RPs, when used fortherapeutic applications should ideally concentrate atthe site of the tumour and result in very minimaldamage to the surrounding cells (Bertrand et al. 2014).The radionuclide emitting high energy a- or b-particlesare generally preferred for large tumours and the onesemitting Auger electrons are useful for small cancerouscells or clusters (Yeong et al. 2014). The commonlyused radionuclides for therapeutic applications alongwith their important physical properties are given inTable 3. The treatment of thyroid cancer by radio-iodine, treatment of solid tumours with radiolabeledmonoclonal antibodies (mAbs), and the palliationtherapy of pain from bone metastases are some of thesignificant therapeutic applications of the RPs (Dan-gelo et al. 2012).Lange et al. reviewed the therapeutic applications of

phosphate-based RPs for the targeted treatment ofpainful bone metastases (Lange et al. 2016). Thebiodistribution and dosimetry studies are important forthe use of these RPs for human administration. Amongthe various phosphate-based RPs, the (177Lu)-

Figure 2. 99mTc-Pyrophosphate-based SPECT combined with multislice CT angiography. (A) Arrows show high-intensityfocal accumulation of the radiopharmaceutical in the middle septal part of the left ventricle and low-intensity accumulation inthe middle septal part and the anterolateral region of the left ventricle. (B) Arrows show diffuse moderate-intensitypathological accumulation of 99mTc-Pyrophosphate in the middle basal part of the left ventricle. (C) Arrows show focalpathological accumulation of 99mTc-Pyrophosphate in the middle part of the right ventricular free wall. Reproduced fromIlyushenkova et al. (2020) under creative commons CC BY license. Copyright � 2020 Julia Ilyushenkova et al.


ethylenediaminetetramethylene phosphonic acid(EDTMP) has obtained approval for clinical use inIndia, while the Samarium-153 (153Sm)-EDTMP hasobtained worldwide marketing authorization (Langeet al. 2016).Alsadik et al. reviewed the application of Peptide

Receptor Radionuclide Therapy (PRRT) for effectivetreatment of metastable and non-operable neuroen-docrine tumours (Alsadik et al. 2019) The treatmentusing PRRT was well tolerated with only mild andreversible side effects (Alsadik et al. 2019). The studyconducted by Incerti et al revealed the application of11C-choline PET/CT (CHO-PET/CT) based helicaltomotherapy (HTT) in the therapy of bone metastasesin recurrent prostate cancer patients. The study con-ducted on 20 patients with recurrent prostate cancerexhibited medium-low toxicity (Incerti et al. 2017).Morgensten et al. described the application of Acti-

nium-225 (225Ac) labeled prostate-specific membraneantigen-617 (PSMA-617) for the treatment and targetedtherapy of metastatic castration-resistant prostate can-cer, bladder cancer, and brain tumours. The imple-mentation of 225Ac-PSMA-617 has proved to be apromising therapeutic option for cancer in men andalso defines the potential of the concept of targeted a-therapy (Morgenstern et al. 2018). In a study conductedby Camacho et al. Bevacizumab, a humanized mono-clonal antibody directed against vascular endothelialgrowth factor was derivatized with DOTA-NHS-esterand subsequently radiolabeled with 177Lu. The 177Lu-DOTA-Bevacizumab was found to be a novel radioimmunotherapeutic agent for melanoma. The com-pound was found to be stable and exhibited high liverand tumour uptake. The promising results obtained inthe study for the 177Lu-DOTA-Bevacizumab proved tobe very effective for melanoma diseases (Camachoet al. 2017).Wu et al. reviewed the application of RPs in the

treatment of hepatocellular carcinoma (HCC) (Wu

et al. 2016). The RPs 131I-labeled Lipiodol and 90Ymicrospheres are used for the trans-arterial radioem-bolization technique employed after surgical treatmentof HCC as adjuvant therapy. The radiopharmaceutical131I-metuximab is currently employed in radioim-munotherapy as a part of the combination therapy ofHCC (Wu et al. 2016).Cives et al. reviewed the application of radionuclide

therapy for the treatment of pancreatic and lung neu-roendocrine tumours (Cives and Strosberg 2017). Theradiopharmaceutical 177Lu-DOTATATE showedexceptional tolerability and efficacy in phase III clinicaltrials for the treatment of patients with progressive andmetastatic neuroendocrine tumours (Cives and Stros-berg 2017). Zhang et al. investigated the dosimetry andsafety of a long-acting radiolabeled somatostatinanalog, 177Lu - 1, 4, 7, 10-tetra-azacyclododecane-1, 4,7, 10-tetraacetic acid-Evans blue-octreotate (177Lu-DOTA-EB-TATE) for the treatment of neuroendocrinetumours. A remarkably high uptake, retention, andincreased accumulation in the kidneys and bone mar-row was shown by 177Lu-DOTA-EB-TATE and therebyshowing its therapeutic potential in peptide receptorradionuclide therapy for neuroendocrine tumours(Zhang et al. 2018a).Hagemann et al. studied the application of

mesothelin (MSLN)-targeted thorium-227 conjugate(BAY 2287411) in patients with ovarian and lungcancer (mesothelioma) (Hagemann et al. 2019). TheBAY 2287411 exhibited enormous antitumour efficacyand was well tolerated on in vivo administration. Thespecific uptake and retention in tumours were shown inbiodistribution studies. The results obtained during thepre-clinical study were found to be promising for thetransition of BAY 2287411 into a Phase I clinical trialprogram in patients with lung and ovarian cancers(Hagemann et al. 2019).Jong et al. reviewed the application of radionuclides

in the treatment of bone pain associated with metastatic

Table 3. Radionuclides in therapeutic applications along with their important physical properties

S. No Radionuclide t1/2/Emission Diagnostic application

1. Re-188 17.0 h/Beta particles In the treatment of liver and bone cancer2. P-32 14.26 days/Beta particles Palliation of pain in metastatic bone cancer3. Lu-177 6.647 days/Beta particles For the treatment of melanoma diseases4. Sr-89 50.53/Beta particles For palliative therapy in bone and prostate cancer5. I-123 13.27 h/Gamma rays For the treatment of thyroid metastases6. Pd-103 16.99 days/Gamma rays For the treatment of early-stage prostate cancer7 Pb-212 10.64 h/Beta particles In targeted treatment of breast and ovarian cancer8. I-131 8.02070 days/Beta particles In the treatment of hepatocellular carcinoma and thyroid carcinoma9. Y-90 64.0 h/Beta particles For the treatment of non-Hodgkin’s lymphoma


prostate cancer.38 The radionuclides 2 Radium-223(223Ra), 12 Rhenium-186 (186Re), Strontium-89 (89Sr),7 Samarium-153 (153Sm), and 2 Rhenium-188 (188Re)were reviewed for their efficacy in palliation ofmalignant bone pain associated with prostate cancer.The study revealed that the response to pain wasgreater than 50–60% in treatment with the RPs. Thehematological study further revealed the absence ofthrombocytopenia during the randomized trials (Jonget al. 2016).The conjugation of Zoledronate with 177Lu has

shown promising results in therapy for painful bonemetastases associated with solid tumours. Khawar et al.in their study based on Preclinical biodistribution anddosimetric analysis showed the potential of [177Lu] Lu-DOTAZOL in the treatment of bone metastases (Khawaret al. 2019). The study revealed the high absorption of[177Lu] Lu-DOTAZOL in bone and fast clearance in thekidney indicating its efficacy and safety in the clinicalsetting (Khawar et al. 2019).Tesson et al. determined the benefits of combining

131I-MIP-1095 with cytotoxic drugs in the treatment ofmetastatic prostate cancer (Tesson et al. 2016). The131I-MIP-1095 is a prostate-specific membrane antigen(PSMA)-targeting radiopharmaceutical having goodactivity against metastatic prostate cancer. The inhibi-tion of the growth of spheroids induced by 131I-MIP-1095 was greatly enhanced by cytotoxic drugs such asolaparib, topotecan, bortezomib, and copper-chelatedform of the oxidizing agent disulfiram (DSF: Cu)(Tesson et al. 2016).Banerjee et al. provided an exhaustive review on the

therapeutic application of 177Lu RPs (Banerjee et al.2015). The low energy of 177Lu beta emissions makesthem quite useful in bone palliation therapy as radiationexposure to non-targeted healthy tissues. A similaradvantage is presented by these RPs in peptide receptorradionuclide therapy owing to the lower dose deliveredin the kidney in comparison to other radionuclides(Banerjee et al. 2015).

2.3 Theranostic applications

Recently, the concept of theranostic RPs has gainedenormous attention. The theranostic applications ofRPs are based on the concept of combining diagnosticproperties with the therapeutic potential of radionu-clides with the purpose to provide dual benefits ofimaging and treatment to the patients (Peitl et al. 2019).The theranostic has received tremendous attentionowing to its multiple benefits and a lot of research is

being done in this field (Turner 2018). The RPs fortheranostic use are especially gaining a lot of attentionin the area of oncology to prolong survival improvequality of life for patients suffering from different typesof cancers worldwide (Chaudhary and Gupta, 2017;Langbein et al. 2019). The commonly used radionu-clides for theranostic applications are given in table 4.The radionuclides based on copper are currently

showing a lot of promise as potential theranostic agentsparticularly 64Cu RPs for the diagnosis and treatmentof prostate, neuroendocrine, and hypoxic tumours(Jadvar et al. 2018). The natural role of copper ions incell proliferation is being suggested by Boschi et al asthe possible reason for the increasing use of copperradionuclide in theranostic applications (Boschi et al.2018). Keinanen et al in their study demonstrated theuse of a single injection of trans-cyclooctene (TCO)-modified immunoconjugate for pre-targeted PETimaging and radiotherapy sequentially administering apair of tetrazine (Tz)-bearing radioligands labeled withthe positron-emitting radiometal copper-64 and thebeta-emitting radiometal 177Lu (Keinanen et al. 2019).Ballinger reviewed the use of somatostatin receptor

targeting peptides for diagnosis and treatment of neu-roendocrine tumours using RPs such as 68Ga-DOTA-TATE and 177Lu-DOTATATE (Ballinger 2018). Theauthors also reported the theranostic application of 123I-metaiodobenzylguanidine in the imaging and treatmentof adrenergic tumours (Ballinger 2018). The resultsobtained in their study by Vimalnath et al. demon-strated the theranostic potential of 141Ce-DOTMP (Ce-141 complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene- phosphonic acid) in cancerpatients who suffered from painful metastatic skeletallesions (Vimalnath et al. 2019). The biodistributionstudy exhibited a very high skeletal localization andretention of 141Ce-DOTMP along with rapid clearancefrom the non-target organs (Vimalnath et al. 2019).Galie et al. investigated the potential use of Phos-

phorus-32 (32P)-ATP as a novel theranostic radiophar-maceutical for the imaging of tumour lesions andsimultaneously causing their destruction by deeplypenetrating the entire tumour parenchyma (Galie et al.2017). The histopathological analysis of the tumoursection as shown in figure 3 indicated that the necroticfraction was increased 2-fold in comparison to othertreatments (Galie et al. 2017).

188Re has gained popularity as an attractive candi-date for use in therapeutic nuclear medicine. The par-ticles emit high energy beta rays with energy rangingbetween 784 keV and 2.12 MeV, sufficient to penetrateand destroy targeted abnormal tissues. 188Re and 99mTc


represent a theranostic pair due to their similar chem-ical properties. The successful application of 188Relabeled therapeutic RPs involves the management ofbone metastasis, various primary tumours, endocoro-nary and rheumatoid arthritis, and interventions (Le-pareur et al. 2019).Kortylewicz et al. exploited the theranostic potential

radioactive guanidine (R)-(–) -5-[125I] iodo-30-O -[2-(e-guanidinohexanoyl) -2-phenylacetyl] -20-deoxyuridinefor the imaging and treatment of neuroblastoma (Kor-tylewicz et al. 2020). The studies carried out in themouse models of neuroblastoma exhibited the goodtherapeutic potential of GPAID. It can also use forSPECT and PET study of neuroblastoma by preparingradiolabeled compounds using a tin precursor ofGPAID and labeling them with suitable radionuclides.Thus, they can be used for targeted radiotherapy usingtreatment doses derived from the imaging data (Kor-tylewicz et al. 2020).Cimini et al. reviewed the use of theranostic RPs in

pediatric oncology. Based on their study, they revealedthe utility of theranostic imaging and radioim-munotherapy in pediatric oncology (Cimini et al.2020).

3. Artificial intelligence and radiopharmaceuticals

Artificial intelligence (AI) has emerged as a promisingtool in the treatment and planning of radiotherapy(Wang et al. 2019a). The researchers have now startedto explore the application of artificial intelligence tocomplex patterns of findings, such as those found atfunctional PET imaging of the brain (Zheng et al.2019). The application of AI in the field of RPs hasresulted in the improvement in the treatment planningworkflow efficiency through automation (Arimuraet al. 2019). The application of AI has particularly

made great strides in cancer imaging in the assessmentof the impact of disease and treatment on adjacentorgans, early detection, and prediction of clinical out-comes (Bi et al. 2019; Deig et al. 2019; Lee et al.2019).Ding et al. developed and validated a deep learning

algorithm for the prediction and diagnosis of Alzhei-mer’s disease (AD) using fluorine 18 (18F) fluo-rodeoxyglucose (FDG) PET of the brain and comparedit with radiologic readers (Ding et al. 2019). Theimaging data were preprocessed by using a grid methodfor patients with Alzheimer’s disease and the Fluorine-18-fluorodeoxyglucose PET images obtained from thegrid method are shown in figure 4. The Convolutionalneural network of InceptionV3 architecture as shown infigure 5 was trained on 90% of Alzheimer’s DiseaseNeuroimaging Initiative (ADNI) (2109 imaging studiesfrom 2005 to 2017, 1002 patients) data set. Theremaining 10% were also tested as the independent testset and their performance was compared to the radio-logic readers. The achievement of 82% specificity at100% sensitivity at an average of 75.8 months beforethe final diagnosis in the analysis of the model indi-cated the ability of the developed model in the earlydiagnosis of Alzheimer’s disease (Ding et al. 2019).Mortensen et al. tested the feasibility and assessment

of prostate cancer in prostate glands by AI-drivenmethods and compared it with the manual procedures(Mortensen et al. 2019). The finding of the studyindicated the utility of obtaining the volume and PETmeasures in a very quick time in comparison to themanual approach (Mortensen et al. 2019). The appli-cation of deep convolutional neural networks trainedwith a large multicenter population was applied byBetancur et al. for the prediction of obstructive diseasefrom myocardial perfusion imaging (MPI). The diseasepredicting abilities by deep learning was higher incomparison to current clinical methods, which

Table 4. Radionuclides in theranostic applications

S. No Radionuclide Theranostic Application

1. Cu-64 In the imaging and treatment of prostate and neuroendocrine tumours2. Ga-68 In the imaging and treatment of adrenergic tumours3. Lu-177 For the bone imaging and arthritis treatment4. Re-186 For bone scintigraphy and palliative therapy in bone metastases5. Ho-166 For the imaging and treatment of liver cancer6. I-131 For the diagnosis and treatment of thyroid cancer7 Ra-223 In imaging and palliative therapy of bone metastases8. Pb-212 In the imaging and treatment of various types of cancers9. I-125 In the imaging and treatment of neuroblastoma

10 I-123 For the diagnosis and therapy of thyroid cancers


demonstrated the potential of deep learning to improveautomatic interpretation of MPI (Betancur et al. 2018).The deep learning algorithm was applied by Gulshan

et al. to detect diabetic retinopathy and diabetic mac-ular edema in retinal fundus photographs (Gulshanet al. 2016). The manual grading obtained by oph-thalmologists was compared with the deep learningalgorithm. Trained on a dataset of 12,8175 retinalimages. The deep CNN trained on a dataset of 12,8175retinal images was found to have high sensitivity and

specificity for detection of referable diabetic retinopa-thy (Gulshan et al. 2016).The application of AI in RPs is growing but certain

challenges remain to be tackled for further explorationof this newly emerging tool for other diagnosticapplications. The generalizability of models, acquisi-tion of sufficient data for representative models, col-lection of multiple types of data, and lack ofinfrastructure in algorithm assessment are some of thebiggest challenges which need to be overcome for

Figure 3. Tumours from 32P-ATP-treated mice exhibited a significantly higher fraction of necrotic areas compared to those fromeither untreated, non-radioactive ATP-treated or PBS-treated mice (A). TUNEL assay on 32P-ATP-treated tumours revealedextensive contiguous DNA-fragmentation other than within grossly necrotic areas (B). Necrosis was restricted to tumours but wascompletely absent in other tissues such as liver (C). In 32P-ATP-treated tumours, necrosis extended over large regions oftencovering the entire tumour core while it appeared fragmented in multiple and small necrotic foci in control tumours (D).Reproduced from Vimalnath et al. (2019) under creative commons CC BY license. �2020 Ivyspring International Publisher.


further exploration of AI in medical imaging applica-tions (https://www.global-engage.com/life-science/four-challenges-in-developing-ai-algorithms-for-medical-imaging/).

4. Carbon dots in imaging and theranostics

Carbon dots represent a new form of nanocarbonmaterials which is emerging as an interesting tool inbioimaging and theranostic (Lim et al. 2015; Rao et al.2018; Wang et al. 2019b). The carbon dots have showna lot of promise when they are combined with targetedtherapeutic moieties. Du et al. reviewed the applica-tions of carbon dots in imaging and drug carriers to

multifunctional theranostic systems (Du et al. 2019).Liu et al. prepared the tyrosine-based carbon dots withphenolic hydroxyl groups and radiolabeled them with125I to form 125I-TCDPEGs which showed excellentbiocompatibility and stability (Liu et al. 2019). Theradioactive carbon dots exhibited a huge potential forcellular fluorescence imaging and SPECT imagingagents for the early diagnosis of tumours. TheTCDPEGs were also found to be feasible with otheriodine radionuclides for different imaging applications(Liu et al. 2019). Zhang et al. comprehensivelyreviewed the utility of other multi-functional Carbon-based nanomaterials such as graphene, fullerenes, andsingle-walled carbon nanotubes in cancer molecularimaging and imaging-guided therapy (Zhang et al.2018b).

Figure 4. Example of fluorine 18 fluorodeoxyglucose PET images from Alzheimer’s Disease Neuroimaging Initiative setpreprocessed with the grid method for patients with Alzheimer disease (AD). One representative zoomed-in section wasprovided for each of three example patients: (A), 76-year-old man with AD, (B), 83-year-old woman with mild cognitiveimpairment (MCI), and, (C), 80-year-old man with non-AD/MCI. In this example, the patient with AD presented slightly lessgray matter than did the patient with non-AD/MCI. The difference between the patient with MCI and the patient with non-AD/MCI appeared minimal to the naked eye. Reproduced with permission from Ding et al. (2019). � RSNA, 2018.


5. Nano radiopharmaceuticals

The application of nanotechnology to RPs has showntremendous potential in imaging and therapeutic (Dattaand Ray 2020). Nanoradiopharmaceuticals are pre-pared by either nanoencapsulating radioactive RPs orthe non-radioactive ligand with a radionuclide.Nanopharmaceuticals are being regarded as the futureof nuclear medicine (Santos-Oliveira 2011). Coelhoet al. developed and evaluated MDP (methyl diphos-phonate) labeled with 99mTc (99mTc MDP) in ratsinduced with bone cancer metastasis and excellentresults were obtained in the patients (Coelho et al.2015). Sarcinelli et al developed the nano radiophar-maceuticals for breast cancer imaging by labeling thepolylactic acid (PLA)/polyvinyl alcohol (PVA)/mont-morillonite (MMT)/trastuzumab nanoparticles with99mTc (Sarcinelli et al. 2016). The cytotoxicity studyexhibited the ability of nanoparticles in reaching breastcancer cells. The biodistribution study showed highrenal clearance and high uptake by the lesions. Thefindings of the study supported the application of PLA/PVA/MMT/trastuzumab nanoparticles in breast cancerimaging (Sarcinelli et al. 2016). Recently, Polyak andRoss reviewed the role of PET and SPECT imagingassociated nanoparticle-based products in radiothera-nostic approaches and imaging-guided therapy (Polyakand Ross 2018).Hu et al. demonstrated the theranostic application of

gadolinium-based nanoparticles (AGuIX) in hepatocel-lular carcinoma (HCC) (Hu et al. 2019). The AGuIXnanoparticles were shown to have enhanced

permeability and retention effects. The effects of radia-tion therapy were assessed by carrying out apoptosisimaging, tumour growth studies, and immunohisto-chemistry to verify the antitumour effects of AGuIX.Apoptosis imaging and immunohistochemistry asshown in figure 6 demonstrated the high degree of cellapoptosis with a high dose of AGuIX-mediated RT. Thepathology and immunohistochemistry of tumour tissuesas shown in figure 7 indicated the statistical differencebetween the RT?AGuIX (10 mg) group and the controlgroup. Overall, the results obtained in the present studyshowed that the AGuIX can facilitate theranostic MRI-radiosensitization in HCC (Hu et al. 2019).Zhao et al. developed multifunctional poly-

ethyleneimine-entrapped gold nanoparticles (AuPENPs) for targeted imaging by SPECT/CT andradionuclide therapy of malignant glioma. The poly-ethyleneimine template was modified with poly-ethylene glycol (PEG), chlorotoxin (specific gliomatargeting ligand), and 3-(4-hydroxyphenyl) propionicacid-Osu (HPAO) was used to entrap gold nanoparti-cles (Zhao et al. 2019). The Au–PE–NPs–CTX wasthen radiolabeled with 131- I and assessed in gliomaC6 cells before and after the radiolabeling. The 131I–Au–PE–NPs–CTX showed high radiochemical purityand stability and had the potential to be used for thetargeted SPECT/CT imaging and radionuclide therapyof glioma cells. The Targeted SPECT imaging ofglioma in an orthotopic rat glioma model as shown infigure 8 revealed the ability of 131I-Au PENPs-CTX incrossing the blood-brain barrier and glioma targeting(Zhao et al. 2019).

Figure 5. Convolutional neural network architecture, Inception V3, used in this study. Inception v3 network stacks 11inception modules where each module consists of pooling layers and convolutional filters with rectified linear units asactivation function. The input of the model is two-dimensional images of 16 horizontal sections of the brain placed on 4 9 4grids as produced by the preprocessing step. Three fully connected layers of size 1024, 512, and 3 are added to the finalconcatenation layer. A dropout with rate of 0.6 is applied before the fully connected layers as means of regularization. Themodel is pretrained on ImageNet dataset and further fine-tuned with a batch size of 8 and learning rate of 0.000 Reproducedwith permission from Ding et al. (2019). � RSNA, 2018.


6. Cornell dots in radio imaging

Cornell dots or C dots are glowing nanoparticles usedin illumination and targeting of cancer cells. The role ofC dots is now being expanded by the researchers intracking different cancer targets through a fluorescence-based multiplexing process. The presence of abundantproteins on a tumour cell surface allows the C dots

made up of silica to effectively track cancer cells. Chenet al. developed the batches of spectrally distinct 6-nmnear-infrared fluorescent core-shell silica nanoparticlesand surface functionalized with different melanomatargeting radionuclides. The developed nanoparticlesaccurately detected the cancerous nodes in a sponta-neous melanoma mini swine model using image-gui-ded multiplexing tools. The study demonstrated the

Figure 6. 99mTc-duramycin SPECT/CT images of the mice in control group and therapy groups before (upper row) andafter (below row) radiation. (A) First panel is the control group with no therapy, 99mTc-duramycin SPECT/CT images and 3days after 99mTc-duramycin SPECT/CT images again. In the rest of the panel, 99mTc-duramycin SPECT/CT images werecompared in each panel 1 day before and 1 day after irradiation, and the three panels showed the images of mice injected bytail vein injection of normal saline 1 mg of AguIX (third panel) and 10 mg of AGuIX (fourth panel), respectively (n = 3). Thesame color scale was applied to each of the images. (B) The tumour-to-background ratio (T/B) was used to express tumoursignal intensity. Independent-sample t test was used for statistics. The asterisk indicates statistical significance (P\ 0.05).Reproduced in original from Polyak and Ross (2018) under creative commons attribution (CC-BY) license. Copyright �2019 Hu, Fu, Liu, Tan, Xiao, Shi and Cheng.


potential of fluorescent nanoparticles in accuratelytargeted disease eradication and patient safety alongwith transforming the surgical decision-making forcancer patients (Chen et al. 2019). Liu et al. used the18F-fluorodeoxyglucose (FDG) intravenously to excitethe ZnGa2O4:Cr

3? nanoparticles (ZGCs) for tumourluminescence imaging (Liu et al. 2020). The author intheir study reported tumour luminescence imaging withhigh sensitivity, high contrast, and minimized radiationexposure to patients prompting the use of image-guidedsurgery in the future (Liu et al. 2020).

7. Regulatory perspectives of RPs

Keeping in view the short half-life, inherent hazardousnature of radioisotope, issue of maintaining sterilitywith radiation safety simultaneously, storage, transport,and water disposal issue and the fact that minutechange in dose may cause faulty diagnosis or evenoverexposure, the guidelines applicable to pharma-ceuticals are not entirely relevant for RPs. This

mandates a regulatory – setup that should cater to thespecific guidelines laid down by not only the pharma-ceutical regulators but also the nuclear regulator of thecountry. Salient features of the regulatory framework ofRPs with special emphasis on their approval proce-dures in the US, EU and India are presented in thefollowing section (Sharma et al. 2017a; Sharma et al.2018; Peitl et al. 2019; Sharma et al. 2019a).

7.1 USA

In the USA, the Centre for Drug Evaluation andResearch (CDER) which is a Department of U.S. Foodand Drug Administration (USFDA) and RadioactiveDrug Research Committee (RDRC) is the main regu-latory bodies involved in the regulation of RPs. Thereare clear-cut and specific guidelines in the USA for theRPs starting from the developmental part and extendthroughout its lifecycle to the ADR reporting. Some ofthe important guidelines on RPs in the USA are asfollows (https://www.fda.gov/regulatory-information/

Figure 7. Pathology and immunohistochemistry of tumour tissues. (A) Microscopic images of TUNEL (9200) staining oftumour tissues obtained from HepG2-bearing mice with no therapy were used as control. In TUNEL staining, apoptotic cellsare stained brown. (B) Data analysis using the H-SCORE of TUNEL staining of tumour tissues to compare the four groups.Independent-sample t test was used for statistics. The asterisk indicates statistical significance (P\ 0.05). Reproduced inoriginal from Hu et al. (2019) under creative commons attribution (CC-BY) license. Copyright � 2019 Hu, Fu, Liu, Tan,Xiao, Shi and Cheng.


search-fda-guidance-documents/compounding-and-repackaging-radiopharmaceuticals-outsourcing-facilities-guidance-industry; https://www.fda.gov/media/102615/download; https://www.fda.gov/regulatory-information/search-fda-guidance-documents/oncology-therapeutic-radiopharmaceuticals-nonclinical-studies-and-labeling-recommendations-guidance; https://www.fda.gov/media/72295/download; https://www.raps.org/news-and-articles/news-articles/2019/8/radiopharmaceuticals-fda-finalizes-guidance-on-no).

• Nuclear Pharmacy Compounding Guidelines, 2001• Procedure Guidelines for Use of RPs, 2001• Developing Medical Imaging Drugs and Biological

Products

• Part 1: Conducting Safety Assessment - June 2004Part 2: Clinical Indication – June 2004Part 3: Design, Analysis, and Interpretation ofClinical Studies – June 2004cGMP for Phase I Investigational Drugs – July 2008

• PET Drugs - Current Good Manufacturing Practice(cGMP), 2009

• Paediatric RPs Administration Dose: North Amer-ican Consensus Guideline - 2010

• PET Drug Applications - Content and Format forNDAs and ANDAs, 2011

• Investigational New Drug Applications for PositronEmission Tomography (PET) Drugs, 2012

• Clinical Trial Imaging Endpoint Process StandardsGuidance for Industry, 2015

Figure 8. In vivo SPECT images of the rat intracranial glioma model treated with (A) 131I-Au PENPs-CTX and (B) 131I-AuPENPs at different time points of 0.5, 2, 4, 6, 8 and 16 h, respectively, and (C) their tumour-to-background ratios (TBR) ofthe SPECT signal intensities in the brains. (D) SPECT images of ex vivo brains at 16 h post injection. Reproduced fromZhao et al. (2019) under Creative Common Attribution CC BY License. Copyright � 2019, Springer Nature.


• Compounding and Repackaging of RPs by State-Licensed Nuclear Pharmacies and Federal Facili-ties, 2016

• Microdose Radiopharmaceutical Diagnostic Drugs:Nonclinical Study Recommendations, 2017

7.1.1 Section and act for RP in the USA: The FDAModernization Act (Public Law 105–115) of 1997 wasthe major regulatory act that gave special mention toPET RPs which were exempted in the past scenariofrom some of the FDA regulations (https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=601&showFR=1&subpartNode=21:7.0.1.1.2.4). Section 121 of the FDA Modernization Actled to reforms in regulation for RPs in the US. Sec-tion 121(c)(1)(A) of this Act directed FDA to establishsuitable approval and review procedures, including theNew Drug Application (NDA) and Abbreviated NewDrug Application (ANDA) for RPs. Also, around thesame time, regulations concerning the manufacture ofPET drugs entitled ‘PET Drugs - Current Good Man-ufacturing Practice’ were announced. The main aim ofthis regulation was to help PET drug manufacturersunderstand the expectations of the FDA concerning themanufacture of such drugs and the suitable procedureand cautions to be followed (PET Drugs, CGMP, 2009)(https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=601&showFR=1&subpartNode=21:7.0.1.1.2.4).21CFR310.3 define radioactive drugs ‘‘means any

substance defined as a drug in section 201(g)(1)of theFederal Food, Drug, and Cosmetic Act which exhibitsspontaneous disintegration of unstable nuclei with theemission of nuclear particles or photons and includesany nonradioactive reagent kit or nuclide generatorwhich is intended to be used in the preparation of anysuch substance but does not include drugs such ascarbon-containing compounds or potassium-contain-ing salts which contain trace quantities of naturallyoccurring radionuclides’’ (Kortylewicz et al. 2020).21CFR601 licensing – Subpart D-Diagnostic RPs andits section 601.31 defined the diagnostic RPs (https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=601&showFR=1&subpartNode=21:7.0.1.1.2.4).

7.1.2 Approval procedure of RP in the USA: In theUSA, the approval of RP proceeds through InvestigationNew Drug (IND) application, Clinical Trials, and thenNew Drug Application (NDA). RPs can be used

clinically in the US if they have an approved NDA orANDA regulatory status. Unapproved PET drugs can beused clinically only under expanded access IND route(Schwarz and Decristoforo 2019). Sometimes NDA orANDAmaynot be possible for clinical use ofRPs, just asin the case of some rare diseases or for an RPwith a shorthalf-life. FDA has addressed these concerns and anotherguideline was released which dealt with IND applicationof unapproved PET drugs and various expanded accessrequirements for their clinical use. Additionally, forresearch-based RPs to be used for human studies, arequirement exists to go for either INDA or radioactivedrug research committee (RDRC) approval. Unap-proved PET drugs can be used clinically only under theexpanded access IND route. RPs approval process in theUSA is a lengthy and cumbersome process, passingthrough an intricate web of many phases, regulatoryauthority clearance and detailed investigations as shownin figure 9 (https://www.fda.gov/drugs/types-applications/investigational-new-drug-ind-application). Forthe approval process of RPs, different pathways existdepending upon the purpose for which RPs are intendedto be used. For research-based RPs to be used for humanstudies not intended for immediate therapeutic, diag-nostic, or similar purposes or to determine the safety andeffectiveness of the radioactive drug or biological pro-duct for such purposes, the requirement exists to go forradioactive drug research committee (RDRC) approvalwhile submitting a traditional IND for general investi-gational use on humans follows specifications as per 21CFR 312. Subsequent to the approval of IND by FDA,clinical trial commences starting from Phase 0 to Phase 3(Agrawal et al. 2019).The major components of eIND and IND approval

process for RPs are:

1. Investigation of a clinical plan, the reason forchoosing the compound, and goal of study

2. Summarized documents of the studies of humansubjects, preclinical, or clinical data.

3. Clinical trial protocol for studies on humans.4. CMC (Chemistry, Manufacturing, and Controls)

documents.5. For toxicity studies, quality control.6. Animal dosimetry (not defined in eIND and IND

requirement section).7. IRB approval.8. CRF (Case Report Form) document that shows the

maintained quality and integrity data

7.1.3 New non-clinical guidance documents for diag-nostic RP: The microdosing and single or infrequent


clinical use of diagnostic RPs has led to the formulationof a new guidance document ‘‘Microdose Radiophar-maceutical (RP) Diagnostic Drugs: Nonclinical StudyRecommendations’’ (Microdose RadiopharmaceuticalDiagnostic Drugs). The main purpose of this newguidance document is to refine the nonclinical studiesrecommendations for diagnostic RPs. The majorhighlight of this guidance document is the eliminationof additional toxicology requirements and clarificationon non-clinical requirements for microdose RPs in the

case of Phase 1–3 clinical trial studies. The separatedraft guidance, ‘‘Oncology Therapeutic RPs: Nonclin-ical Studies and Labeling Recommendations, forradiotherapeutics’’ has been published by the US FDAwith a purpose to help the sponsors in designing appro-priate nonclinical studies before initiation of human (trialsstudy and then continue through product approval(https://www.fda.gov/regulatory-information/search-fda-guidance-documents/microdose-radiopharmaceutical-diagnostic-drugs-nonclinical-study-recommendations;

Figure 9. The approval process of the RPs in USA.


https://www.raps.org/news-and-articles/news-articles/2018/8/microdose-radiopharmaceutical-diagnostic-drugs-fd).

7.2 Europe

EudraLex, consisting of rules and regulations govern-ing medicinal products, provides the legal frameworkfor the established use of medicinal compounds inEurope. It consists of volumes and directives. Theregulatory setup in the European Union (EU) is relatedto these legislations and harmonization amongst themembers of the EU. The European Medicine Agency(EMA) is the main regulatory agency of RP. It is adecentralized agency of the EU and is accountable forall sorts of scientific evaluation, supervision as well assafety monitoring of medicines across the EU states.The EMA adopts various opinions which are thenratified into legally binding decisions by the EuropeanCommission (EC). The Committee for MedicinalProducts for Human Use (CHMP) at the EMA has aspecific drafting group that is responsible for draftingguidelines relating to RPs (EMEA, 2007). The othercommittee is CHMP (Committee for Medicinal Prod-ucts for Human Use) help in drafting guidance docu-ment for the RP. The approval of RP follows the samepath of the decentralized or centralized procedure as isfollowed for conventional drug approval. The majorguidelines on RPs are as follows (https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-radiopharmaceuticals-revision-1_en.pdf; https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-radiopharmaceuticals_en.pdf; https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines/clinical-efficacy-safety/clinical-efficacy-safety-radiopharmaceuticals-diagnostic-agents).

• Guidelines on Current Good Radio PharmacyPractice (cGRPP) in the Preparation of RPs, 2007.

• EU Guidelines to Good Manufacturing Practice,Annex 3: Manufacture of RPs, 2008.

• Guideline on RPs for Marketing Authorization,2008.

• Guideline to Regulations for RPs in Early PhaseClinical Trials in the EU, 2008.

• Guideline on Clinical Evaluation of DiagnosticAgents: Committee for Medicinal Products forHuman Use, 2009.

• Guidance on Current Good Radio Pharmacy Prac-tice (cGRPP) for the small-scale Preparation ofRPs, 2010.

• Guideline on core SmPC and Package Leaflet forRPs, 2011.

• Guideline on the Acceptability of Names forHuman Medicinal Products Processed through theCentralized Procedure, 2014.

• EANM Guideline for the Preparation of an Investi-gational Medicinal Product Dossier (IMPD), 2014.

• Concept Paper on the Development of Guidance onthe Non-clinical Evaluation of RPs, 2017.

• Guideline on the Requirements for the Chemicaland Pharmaceutical Quality Documentation con-cerning Investigational Medicinal Products in Clin-ical Trials, 2017.

• European Medicines Agency preauthorization Pro-cedural Advice for users of the Centralized Proce-dure, 2017.

7.2.1 New regulation for diagnostic RP: The ‘‘clinicaltrial regulation’’ was referred to in Regulation536/2014 but it was old regulations. The new regula-tion is formed by incorporation of some change inold regulation and new regulation is Directive2001/20. The new regulations have no implicationson therapeutic RPs which will continue to be con-sidered in the same way as the conventional medicalproducts. However, there are some substantialchanges in new regulations for the diagnostic RPwhich according to Penuelas et al are as follows(Penuelas et al. 2019):

1. Exemption for marketing authorization for manu-facturing and import of Investigation MedicinalProducts (IMPs) in case of diagnostic RPs forclinical trial purposes.

2. Exemption from GMP production of the RPsincluded in the exception of art 61.

3. Easy and simple labeling of diagnostic RPs.

7.2.2 Approval of RP in Europe (Kristensen 1992;Schwarz et al. 2019): Any RP may be placed in the EUmarket only when a marketing authorization orapproval has been issued to it. For this, approval in aone-member state can be obtained by national autho-rization, while approval in several or all member statescan be obtained either by Mutual Recognition Proce-dure (MRP), Centralized Procedure (CP), or using theDecentralized Procedure (DP). Thus, there are severaloptions for seeking approval in the EU market. EUgives the proper guidelines for the preclinical (earlyphase) trials. The clinical trial is initiated in the EUafter submitting a clinical trial application to the


competent national authority (Arimura et al. 2019).The approval of clinical trials is done by ‘‘scientificadvice’’ as shown in figure 10. EudraCT ‘‘EuropeanClinical Trials Database’’ needs three types ofdocuments:

1. The clinical document (GCP, CRF, InformedConsent Form, etc)

2. The central document described under IMPDIMPD (Investigational Medicinal Product Dossier)contains 2 types of documents

• Chemical and Pharmaceutical documentsSafety data of the investigated medicinalproduct

3. Investigation brochure

7.3 Regulation of RPs in India

RPs are regulated in India by the ‘‘Atomic EnergyRegulatory Board’’ (AERB), which is a supreme boardof the ‘‘Department of Atomic Energy, Government ofIndia’’. In Nov 1983, AERB was established by thePresident of India by exercising the powers granted by‘‘Section 27 of Atomic Energy Act, 1962’’ and carriesvarious regulatory work and safety information of the‘‘Atomic Energy Act, 1962’’. The administrative role ofAERB is to determine the rules and declare notifica-tions under ‘‘Atomic Energy Act, 1962 and Environ-ment (Protection) Act, 1986’’ (https://www.aerb.gov.in/english/acts-regulations/acts; https://www.aerb.gov.in/english/acts-regulations/rules).The Board of Radiation and Isotopic Studies (BRIT)

is an independent unit of the DAE, Government ofIndia, which caters to the requirements of products andservices based on radiation and isotopes in India. Inconjunction with the RPs Division of the BhabhaAtomic Research Center (BARC), Mumbai, it carriesout the development, production, and supply of RPs tomany nuclear medicine centers throughout the country.BARC supplies reactor-produced radioisotopes toBRIT, where they are processed leading to the pro-duction of RPs for their multifarious applications inhealthcare and industry (https://www.britatom.gov.in/htmldocs/products01/html). The 78th meeting of DrugsTechnical Advisory Board (DTAB) held on February12, 2018, at DGHS, Nirman Bhawan, New Delhi,considered the establishment of a full-fledged wing atthe CDSCO for regulations of RPs which shall work inconjunction with DAE for exercising various regula-tory controls on RPs (https://cdsco.gov.in/opencms/

resources/UploadCDSCOWeb/2018/UploadCommitteeFiles/78thDTAB.pdf).In Indian Pharmacopeia-2014, one general chap-

ter for the RPs and 19 monographs of RPs, wasintroduced following an exhaustive consultation withthe Indian Pharmacopoeia Expert Committee onRadiopharmaceuticals (ECRP). 10 more RPs wereadded in its addendum 2015. After that in addendum2016, 3 more RPs were included (Meher 2020). Threemore radiopharmaceutical monographs were added inIndian Pharmacopeia 2018.

7.3.1 Role of Bhabha Atomic Research Centre (BARC)and Central Drug Standard Control Organisation(CDSCO) in regulations: BARC is an importantresearch center of the ‘‘Department of Atomic Energy’’which supervises the usage of radioactive material andsupports the various applications of radio medicine(Meher 2020). ‘‘Central Drug Standard Controlorganisation’’ (CDSCO) under ‘‘Ministry of Health andFamily Welfare, Government of India’’ with its Drugand Cosmetic Act 1940 and rules framed thereunder isa key player to supervise RPs in India (https://www.barc.gov.in.about/index.html).

7.3.2 Regulatory challenges for RPs in India: Due tothe increasing demand for RPs, India requires a strong

Figure 10. The approval of clinical trials application inEU.


regulatory setup for RPs. Since initially, Radiation Med-icine Centre (RMC) of BARC at Tata Memorial Centre,Parel and Institute of Nuclear Medicine and Allied Sci-ence (INMAS), Defense Research and DevelopmentOrganisation (DRDO)weremainly involved in producingRPs, BARC has been mandated the task of regulating theRPs through Radiopharmaceutical Committee (RPC),wherein CDSCO is also represented. The present regu-latory arrangement has fewer contradictions and lacunaswhich complicate the issues and consequently dissuadesthe producer and specialists from putting resources intoradiopharmaceutical space. The biggest challenge for theradiopharmaceutical in the Indian regulations is the factthat theRPs are exempted from the scope of theDrugs andCosmetic Act 1940 and the associated rules which areotherwise applicable to all other drug and cosmeticproducts. RPs are placed in Schedule K of the Drug andCosmetic Act under serial number 20. This provides anexemption to RPs as a class from the provisions ofChapter IVof the Act and rules made thereunder relatingto their manufacture and sale. This is most probably donesince it is believed that the Drug Controller General ofIndia (DCGI) does not have adequate expertise in regu-lating RPs. Since hitherto, the Department of AtomicEnergy (DAE) units and INMAS, DRDO were the onlyones producing it in the government sector, RPC wasadequate in regulating. However, in the 21st century,many private players have chipped in including Healthfacilities Hospital cyclotrons, making it necessary for theGovernment to amend theAct to accord the full status of adrug to RPs because of the diverse and growing roles ofRPs in diagnosis and treatments. In the current setup,permission for manufacturing needs to be obtained fromAERB, while the approval of DCGI is a must forlaunching the product in the Indian market. Official statushas been now accorded to RPs by including variousmonographs in the last decade in Indian Pharmacopoeia.Non-implementation by drug control organisations is aserious ambiguity needing urgent attention. The lack ofcoordination between the nuclear regulators (AERB) andpharmaceutical regulators (CDSCO) who have tried toexercise their regulatory control on RPs in the recent pasthas led to widespread repercussions in the nuclear medi-cine community (Sharma et al. 2019b). The guidelinesadministeringRPs in India needobvious data for initiatingpreclinical clinical examinations, clinical preliminaries,and different bioavailability and bioequivalence studies(Sharma et al. 2017).

7.3.3 eLORA system of e-licensing of radiation appli-cations: In the last decade, the application of ionizationradiation techniques related to the department of

medicine, industry, and research has substantiallyincreased in India. These applications have been col-lected with great social benefits in terms of cancertreatment, diagnosis, and industrial use such as non-destructive testing, gauging and food processingapplications, etc. The enhancement in the use of ion-izing radiation technology has created a dreadfulchallenge to the AERB in regulating all these newfacilities with a purpose to ensure the security andsafety of radiation technology. To compete with thechallenges, AERB took the first step with thee-Governance system, eLORA (e-Licensing of Radia-tion application) to computerization of regulatory pro-cedure in India related to the utilization of the ionizingradiation (https://www.aerb.gov.in/english/elora). Asper AERB announcement dated 10 September 2014,license for operation of all medical radiation facilities(diagnostic radiology/radiotherapy/nuclear medicine)in India has to be obtained using the e-Licensing ofRadiation Applications (acronym as ‘eLORA’) plat-form which is a web-based application on the AERBwebsite (Aggarwal et al. 2017).eLORA is the online procedure for licensing appli-

cation, it used to make the direct communication linkwith the stakeholder and AERB for exchange thecommunication and information transaction for givingits regulatory services, its higher efficiency and trans-parency in the application form. The framework ofeLORA system is related to essential technology whichwas helpful in attaining cost-effectiveness at theinvestment point of view and further during operationat the data centre. The eLORA system is as per lawfulrequirements grant by the Government of India (Ag-garwal et al. 2017).

7.3.4 Marketing authorization of RPs in India: Todate, there is no clear-cut regulatory guideline for theapproval process of RPs in India. Nuclear medicinepractitioners prefer to use new discoveries in RPs ontheir own patients instead of seeking approvals forcommercialization. Due to the multiple controls ofdifferent non-overlapping agencies like BARC, RPC,RMC and CDSCO, major lacunas and sometimesconfusion exists among the market players about theexact regulatory requirements to be followed for suc-cessfully launching their radiopharmaceutical productinto the Indian market. For any new drug approval,permission is taken from the licensing authority orDCGI by submission of Form 44 and other relatedinformation as prescribed in ‘‘Schedule Y of Drug andCosmetic Act 1940 and Rules 1945’’. But in the case ofRPs, the DCGI gives the power of approval of


concerned RP to BARC (Sharma et al. 2019b). Theapproval procedure of RPs in India is shownschematically in figure 11.

8. Conclusion and future perspective

RPs in recent years have successfully emerged as animportant tool for the diagnosis and treatment of vari-ous medical conditions. Not only are they progres-sively being used for the diagnosis of various criticaldiseases but their therapeutic application in varioustypes of cancers and bone pain palliation associated

with skeletal metastasis and hyperthyroidism has alsoattained massive success. The emergence of theranosticagents in which the combination of diagnostic andtherapeutic RPs providing more personalized treatmentto the patient has resulted in a new lead to the scientificfraternity in the field of nuclear medicine. Recently, theuse of artificial intelligence, nanoradiopharmaceuticalsand carbon dots has broadened the spectrum foradvanced research in RPs. However, despite recentadvances in this field, a certain challenge associatedwith the design and regulatory hurdles needs to beaddressed for an explorative and elaborative use ofthese agents. The role of regulatory authorities is very

Figure 11. The approval procedure of RPs in India.


significant in regulating various aspects of RPs. In thisreview, the authors have discussed all these aspects ofradiopharmaceuticals with special focus on applica-tions and regulatory information. With the review ofavailable literature, it can be concluded that there is aneed to revisit the entire corpus of limited regulatoryguidelines for RPs, particularly in the Indian scenarioas it is still inadequate in comparison to the US and EU.The design of better radiotherapeutic agents requirescoordination between the radiopharmaceutical indus-tries, regulatory bodies and nuclear medicine associa-tions of the respective country.

References

Agrawal K, Meher BR and Padhy BM 2019 Ethicalconundrum in nuclear medicine research in India. IndianJ. Nucl. Med. 34 83–85

Aggarwal R, George RA, Alam A and Soni BK 2017E-Licensing of radiation applications (eLORA) in armedforces hospitals: ‘Nuts and Bolts’. Med. J. Armed. ForcesIndia 73 80–84

Alsadik S, Yusuf F and Al-Nahhas A 2019 Peptide receptorradionuclide therapy for pancreatic neuroendocrinetumours. Curr. Radiopharm. 12 126–134

Alsharef S, Alanazi M, Alharthi F, Qandil D and QushawyM 2020 Review about radiopharmaceuticals: Preparation,radioactivity, and applications. Int. J. App. Pharm. 128–15

Arimura H, Soufi M, Kamezawa H, Ninomiya K andYamada M 2019 Radiomics with artificial intelligence forprecision medicine in radiation therapy. J. Radiat. Res. 60150–157

Ballinger JR 2018 Theranostic radiopharmaceuticals: estab-lished agents in current use. Br. J. Radiol. 9120170969–20170985

Banerjee S, Pillai MRA and Russ Knapp FF 2015 Lutetium-177 therapeutic radiopharmaceuticals: Linking chemistry,radiochemistry, and practical applications. Chem. Rev. 1152934–2974

Bertrand N, Wu J, Xu X, Kamaly N and Farokhzad OC 2014Cancer nanotechnology: The impact of passive and activetargeting in the era of modern cancer biology. Adv. DrugDeliv. Rev. 66 2–25

Betancur J, Commandeur F, Motlagh M, et al. 2018Deep learning for prediction of obstructive diseasefrom fast myocardial perfusion SPECT: A multi-center study. JACC Cardiovasc. Imaging 111654–1663

Bi WL, Hosny A, Schabath MB, et al. 2019 Artificialintelligence in cancer imaging: Clinical challenges andapplications. CA Cancer J. Clin. 69 127–157

Biaoxue R, Xiguang C and Shuanying Y 2014 Annexin A1in malignant tumors: Current opinions and controversies.Int. Biol. Markers 29 e8–e20

Boschi A, Martini P, Janevik-Ivanovska E and Duatti A2018 The emerging role of copper-64 radiopharmaceuti-cals as cancer theranostics. Drug Discov. Today 231489–1501

Camacho X, Calzada V, Fernandez M, Sathekge M, KrolickiL and Bruchertseifer F 2017 177Lu-DOTA-Bevacizumab:Radioimmunotherapy agent for melanoma. Curr. Radio-pharm. 10 21–28

Carollo A, Papi S, Grana CM, Mansi L and Chinol M 2019State of the art and recent developments of radiopharma-ceuticals for pancreatic neuroendocrine tumors imaging.Curr. Radiopharm. 12 107–125

Chen F 2019 Preparation and SPECT imaging of the novelAnxa 1-targeted probe 99mTc-p-SCN-Bn-DTPA-GGGRDN-IF7. J. Radioanal. Nucl. Chem. 320 525–530

Chen F, Madajewski B, Ma K, et al. 2019 Molecularphenotyping and image-guided surgical treatment ofmelanoma using spectrally distinct ultrasmall core-shellsilica nanoparticles. Sci. Adv. 5 1–20

Chen F, Xiao Y, Shao K, Zhu B and Jiang M 2020 PETimaging of a novel anxal-targeted peptide 18F-Al-NODA-Bn-p-SCN-GGGRDN-IF7 in A431 cancer mouse mod-els. J. Label. Comp. Radiopharm. (in press)

Choudhury P and Gupta M 2017 Personalized and precisionmedicine in cancer: A theranostic approach. Curr. Radio-pharm. 10 166-170

Cimini A, Ricci M, Chiaravalloti A, Filippi L and SchillaciO 2020 Theragnostic aspects and radioimmunotherapy inpediatric tumors. Int. J. Mol. Sci. 21 3849–3866

Cives M and Strosberg J 2017 Radionuclide therapy forneuroendocrine tumors. Curr. Oncol. Rep. 19 9–17

Coelho BF, Marta de Souza A, Iscaife A, Leite KRM, deSouza Junqueira M, Bernardes ES, da Saliva EO andSantos-Oliveira R 2015 Nano radiopharmaceuticals forbone cancer metastasis imaging. Curr. Cancer DrugTargets 15 445–449

Crestoni ME 2018 Radiopharmaceuticals for diagnosis andtherapy In: Reference Module in Chemistry, MolecularSciences and Chemical Engineering; Elsevier: Oxford,UK

D’angelo G, Sciuto R, Salvatori M, Sperduti I, Mantini G,Maini CL, Mariani G 2012 Targeted ‘‘bone-seeking’’radiopharmaceuticals for palliative treatment of bonemetastases: A systematic review and meta-analysis. J.Nuclear Med. Mol. Imaging 56 538–543

Datta P and Ray S 2020 Nanoparticulate formulations ofradiopharmaceuticals: Strategy to improve targeting andbiodistribution properties. J. Label. Comp. Radiopharm.63 333–355

de Jonga J, Oprea-Lagerb DE, Hooftc L, de Klerkd JMH,Bloemendale HJ, Verheula HMW, Hoekstrab OS and vanden Eertwegh AJM 2016 Radiopharmaceuticals for


palliation of bone pain in patients with castration-resistantprostate cancer metastatic to bone: A systematic review.Eur. Urol. 70 416–426

Deig CR, Kanwar A and Thompson RF 2019 Artificialintelligence in radiation oncology. Hematol. Oncol. Clin.North Am. 33 1095–1104

Ding Y, Sohn JH, Kawczynski MG, et al. 2019 A deeplearning model to predict a diagnosis of Alzheimerdisease by using 18F-FDG PET of the brain. Radiology290 456–464

Drozdovitch V, Brill AB, Callahan RJ, et al. 2015 Use ofradiopharmaceuticals in diagnostic nuclear medicine inthe United States: 1960–2010. Health Phys. 108 520–537

Du JJ, Xu N, Fan J, Sun Wand Peng X 2019 Carbon dots forin vivo bioimaging and theranostics. J. Small 151805087–1805094

Ercan MT and Caglar M 2000 Therapeutic radiopharma-ceuticals. Curr. Pharm. Des. 6 1085–1121

Fan D, Wang K, Gao H, Luo Q, Wang X, Li X, Tong W,Zhang X, Luo C, Yang G, Ai L and Shi J 2020 A 64Cu-porphyrin-based dual-modal molecular probe with inte-grin avb3 targeting function for tumor imaging. J. Label.Compd. Radiopharm. 63 212–221

Fang W and Liu S 2019 New 99mTc radiotracers formyocardial perfusion imaging by SPECT. Curr. Radio-pharm. 12 171–186

Farzin L, Sheibani S, Moassesi ME and Shamsipur M 2019An overview of nanoscale radionuclides and radiolabelednanomaterials commonly used for nuclear molecularimaging and therapeutic functions. J. Biomed. Mater.Res. 107 251–285

Galie M, Boschi F, Scambi I, Merigo F, Marzola P, AltabellaL, Lavagnolo U, Sbatbati A and Spinelli AE 2017Theranostic role of 32P-ATP as radiopharmaceutical forthe induction of massive cell death within avascular tumorcore. Theranostics 7 4399–4409

Gulshan V, Peng L, Coram M, et al. 2016 Development andvalidation of a deep learning algorithm for detection ofdiabetic retinopathy in retinal fundus photographs. JAMA316 2402–2410

Hagemann UB, Ellinsen C, Schuhmacher J, et al. 2019Mesothelin-targeted Thorium-227 conjugate (MSLN-TTC): Preclinical evaluation of a new targeted alphatherapy for mesothelin-positive cancers. Clin. CancerRes. 25 4723–4734

Hu P, Fu Z, Liu G, Tan H, Xiao J, Shi H and Cheng D 2019Gadolinium-based nanoparticles for theranostic MRI-guided radiosensitization in hepatocellular carci-noma. Front. Bioeng. Biotechnol. 7 368–382

Ilyushenkova J, Sazonova S, Zavadovsky K, Batalov R,Rigivskaya Y, Anfinogenova Y and Lishmanov Y 2020Diagnostic efficacy of cardiac scintigraphy with 99mtc-pyrophosphate for latent myocardial inflammation inpatients with atrial fibrillation. Cardiol. Res. Pract. 15983751–5983764

Incerti E, Gangemi V, Mapelli P, et al. 2017 11C-CholinePET/CT based helical tomotherapy as treatment approachfor bone metastases in recurrent prostate cancer patients.Curr. Radiopharm. 10 195–202

Indian Pharmacopoeia 2018 Ministry of Health and FamilyWelfare, Government of India, Ghaziabad

Jadvar H, Chen X, Cai W and Mahmood U 2018Radiotheranostics in cancer diagnosis and manage-ment. Radiol. 286 388–400

Keinanen O, Brennan JM, Membreno R, Fung K, Gangan-gari K, Dayts EJ, Williams CJ and Zeglis BM 2019 Dualradionuclide theranostic pretargeting. Mol. Pharm. 164416–4421

Keresztes A, Borics A and Tomboly C 2015 Therapeutic anddiagnostic radiopharmaceuticals. Biol. 1 225–247

Khawar A, Eppard E, Roesch F, Ahmadzadehfar H, KurpigS, Meisenheimer M, Gaertner FC, Essler M and Bund-schuh RA 2019 Biodistribution and post-therapy dosi-metric analysis of [177Lu] Lu-DOTA ZOL in patients withosteoblastic metastases: First Results. Eur. J. Nucl. Med.Mol. Imaging Res. 102 9–28

Kortylewicz ZP, Coulter DW and Han G, Baranowska-Kortylewicz J 2020 Radiolabeled (R)-(–) -5-iodo-30-O -[2-(e-guanidinohexanoyl)-2-phenylacetyl]-20-deoxyuri-dine: A new theranostic for neuroblastoma. J. Label.Comp. Radiopharm. 63 312–324

Kostenikov NA, Zhuikov BL, Chudakov VM, IliuschenkoYR, Shatik SV, Zaitsev VV, Sysoev DS and StanzhevskiyAA 2019 Application of 82Sr/82Rb generator in neuroon-cology. Brain Behav. 9 e01212–e01224

Kristensen K 1992 European regulations and guidelines forthe registration of radiopharmaceuticals. In: SchubigerPA, Westera G, eds. Progress in Radiopharmacy. Devel-opments in Nuclear Medicine 22p

Langbein T, Weber WA and Eiber M 2019 Future oftheranostics: An outlook on precision oncology in nuclearmedicine. J. Nucl. Med. 60 13S–19S

Lange R, Ter Heine R, Knapp RF, de Klerk JMH,Bloemendal HJ and Hendrikse NH 2016 Pharmaceuticaland clinical development of phosphonate-based radio-pharmaceuticals for the targeted treatment of bonemetastases. Bone 91 159–179

Laudicella R, Baratto L, Minutoli F, Baldari S and Iagaru A2020 Malignant cutaneous melanoma: Updates in PETImaging. Curr. Radiopharm. 13 14–23

Lee LIT, Kanthasamy S, Ayyalaraju RS and Ganatra R 2019The current state of artificial intelligence in medicalimaging and nuclear medicine. British J. Radiol. 1 37–54

Lepareur N, Lacoeuille F, Bouvry C, Hindre F, Garcion E,Cherel M, Noiret N, Garin E and Russ Knapp Jr. FF 2019Rhenium-188 labeled radiopharmaceuticals: current clin-ical applications in oncology and promising perspectives.Front. Med. 6 132–151

Lim SY, Shen W and Gao Z 2015 Carbon quantum dots andtheir applications. Chem. Soc. Res. 44 362–381


Liu N, Shi J, Wang Q, Guo J, Hou Z, Su X, Zhang H andSun X 2020 In vivo repeatedly activated persistentluminescence nanoparticles by radiopharmaceuticals forlong-lasting tumor optical imaging. Small 16 1–18

Liu N, Shi Y, Guo J, Li H, Wang Q, Song M, Shi Z, He L, SuX, Xie J and Sun X 2019 Radioiodinated tyrosine-basedcarbon dots with efficient renal clearance for singlephoton emission computed tomography of tumor. NanoRes 12 3037–3043

Meher BR 2020 Inclusion of radiopharmaceuticals in theIndian pharmacopeia: A step forward. Indian J. Nucl.Med. 35 1–3

Morgenstern A, Apostolidis C, Kratochwil C, Sathekge M,Krolicki L and Bruchertseifer F 2018 An overview oftargeted alpha therapy with 225Actinium and 213Bismuth.Curr. Radiopharm. 11 200–208

Mortensen MA, Borrelli P, Poulsen MH, Gerke O, EnqvistO, Ulen J, Tragardh E, Constantinescu C, EdenbrandtL, Lund L and Høilund-Carlsen PF 2019 Artificialintelligence-based versus manual assessment of prostatecancer in the prostate gland: A method comparison study.Clin. Physiol. Funct. Imaging 39 399–406

Pascu S and Dilworth J 2014 Recent developments in PETand SPECT imaging. J. Label. Compd. Radiopharm. 57191–194

Payolla FB, Massabni AC and Orvig C 2019 Radiopharma-ceuticals for diagnosis in nuclear medicine: A shortreview. Ecletica Quim. J. 44 11–19

Peitl PK, Rangger C, Garnuszek P, Mikolajczak R,Hubalewska-Dydejczyk A, Maina T, Erba T and Decrito-foro C 2019 Clinical translation of theranostic radiophar-maceuticals: Current regulatory status and recentexamples. J. Label. Comp. Radiopharm. 62 673–683

Penuelas I, Vugts DJ, Decristoforo C and Elsinga PH 2019The new Regulation on clinical trials in relation toradiopharmaceuticals: When and how will it be imple-mented? Eur. J. Nuclear Med. Mol. Radiopharm.Chem. 4 40–60

Polyak A and Ross TL 2018 Nanoparticles for SPECT andPET imaging: Towards personalized medicine and ther-anostics. Curr. Med. Chem. 25 4328–4353

Puttemans J, Lahoutte T, D’Huyvetter M and Devoogdt N2019 Beyond the barrier: Targeted radionuclide therapy inbrain tumors and metastases. Pharm. 11 376–399

Ramamoorthy N 2018 Impact of nuclear medicine andradiopharmaceuticals on health-care delivery: Advances,lessons, and need for an objective value-matrix. Indian J.Nuclear Med. 33 273–285

Rao R, Pint CL, Islam AE, et al. 2018 Carbon nanotubes andrelated nanomaterials: critical advances and challenges forsynthesis toward mainstream commercial applica-tions. ACS Nano 12 11756–11784

Sager O, Dincoglan F, Demiral S, Uysal B, Gamsiz H, ElcimY, Gundem E, Dirican B and Beyzadeoglu M 2019 Utilityof molecular imaging with 2-Deoxy-2-[Fluorine-18]

Fluoro-D-glucose positron emission tomography (18F-FDG PET) for small cell lung cancer (SCLC): A radiationoncology perspective. Curr. Radiopharm. 12 4–10

Santos-Oliveira R 2011 Nanoradiopharmaceuticals: Is thatthe future for nuclear medicine? Curr. Radiopharm. 4140–143

Sarcinelli MA, Marta de Souza A, Szwed M, Iscaife A, LeiteKRM, de Souza Junqueira M, da Silva OE, Tavares MIBand Santos-Oliveira R 2016 Nanoradiopharmaceuticalsfor breast cancer imaging: development, characterization,and imaging in inducted animals. Onco. Targets Ther. 95847–5854

Schwarz SW and Decristoforo C 2019 US and EU radio-pharmaceutical diagnostic and therapeutic nonclinicalstudy requirements for clinical trials authorizations andmarketing authorizations. Eur. J. Nucl. Med. Mol. Imag-ing Radiopharm. Chem. 4 10–25

Schwarz SW, Decristoforo C, Goodbody AE, Singhal N,Saliba S, Ruddock PS, Zukotynski K and Ross AA 2019Harmonization of US, European Union, and Canadianfirst-in-human regulatory requirements for radiopharma-ceuticals: Is this possible? J. Nuclear Med. 60 158–166

Shamsel-Din HA, Gizawy MA, Zaki EG and Elgendy A2020 A novel 99mTc-diester complex as tumor targetingagent: Synthesis, radiolabeling, and biological distribu-tion study. J. Label. Compd. Radiopharm. 63 376–385

Sharma N, Kaur H and Sharma RK 2017a Radiopharma-ceuticals regulations: Current scenario and the wayforward. App. Clin. Res. Clin. Trials Reg. Affairs 4183–194

Sharma S, Baldi A and Sharma RK 2017b Radiopharma-ceuticals regulations on bioavailability and bioequiva-lence: present status and future requirements. Mod. Appl.Bioequiv. Availab. 1 555–567

Sharma S, Baldi A, Singh RK and Sharma RK 2018Regulatory framework of radiopharmaceuticals: Currentstatus and future recommendations. Res. J. Life Sci.Bioinformatics. Pharm. Chem. Sci. 4 275–290

Sharma S, Jain S, Baldi A, Singh RK and Sharma RK 2019aIntricacies in the approval of radiopharmaceuticals-Reg-ulatory perspectives and the way forward. Curr. Sci. 11647–55

Sharma S, Rajan MGR, Baldi A, Singh RK and Sharma RK2019b The regulatory dilemma for import of radiophar-maceuticals in India. Curr. Sci. 116 1787–1789

Shi S, Zhang L, Wu Z, Zhang A, Hong H, Choi SR, Zhu Land Kung HF 2020 [68Ga] Ga-HBED-CC-Di Asp: A newrenal function imaging agent. Nuclear Med. Biol. 82–8317–24

Sugimoto MA, Vago JP, Teixeira MM and Sousa LP 2016Annexin A1 and the resolution of inflammation: Modu-lation of neutrophil recruitment, apoptosis, and clearance.J. Immunol. Res. 8239258 1–13

Tesson M, Rae C, Nixon C, Babich JW and Mairs RJ 2016Preliminary evaluation of prostate-targeted radiotherapy


using 131I-MIP-1095 in combination with radiosensitisingchemotherapeutic drugs. J. Pharm. Pharmacol. 68912–921

Turner JH 2018 Recent advances in theranostics andchallenges for the future. Br. J. Radiol. 9120170893–20170902

Vermeulen K, Vandamme M, Bormans G and Cleeren F2019 Design and challenges of radiopharmaceuti-cals. Semin. Nucl. Med. 49 339–356

Vimalnath KV, Rajeswari A, Sarma HD, Dash A andChakraborty S 2019 Ce-141-labeled DOTMP: A thera-nostic option in management of pain due to skeletalmetastases. J. Label. Comp. Radiopharm. 62 178–189

Wang C, Zhu X, Hong JC and Zheng D 2019a Artificialintelligence in radiotherapy treatment planning: presentand future. Technol. Cancer Res. Treat. 18 1–12

Wang X, Feng Y, Dong P and Huang J 2019b A mini reviewon carbon quantum dots: Preparation, properties, andelectrocatalytic application. Front. Chem. 7 671–682

Wu L, Shen F, Xia Y and Yang Y-F 2016 Evolving role ofradiopharmaceuticals in hepatocellular carcinoma treat-ment. Anticancer Agents Med. Chem. 16 1155–1165

Yeong CH, Cheng MH and Ng KH 2014 Therapeuticradionuclides in nuclear medicine: Current and futureprospects. J. Zhejiang Univ. Sci. B 15 845–863

Zhang XM, Zhang HH, Mcleroth P, Berkowitz RD, MontMA, Stabin MG, Siegel BA, Alavi A, Barnett TM, Gelb J,Petit C, Spaltro J, Cho SY, Pomper MG, Conklin JJ,Bettegowda C and Saha S 2016 [124I] FIAU: Humandosimetry and infection imaging in patients with sus-pected prosthetic joint infection. Nuclear Med. Biol. 43273–279

Zhang J, Wang H, Jacobson O, Cheng O, Niu G, Li F, Bai C,Zhu Z and Chen X 2018a Safety, pharmacokinetics, anddosimetry of a long-acting radiolabeled somatostatinanalog 177Lu-DOTA-EB-TATE in patients with advancedmetastatic neuroendocrine tumors. J. Nucl. Med. 591699–1705

Zhang Y, Wu M, Wu M, Zhu J and Zhang X 2018bMultifunctional carbon-based nanomaterials: applicationsin biomolecular imaging and therapy. ACS Omega 39126–9145

Zhao L, Li Y, Zhu J, Sun N, Song N, Xing Y, Huang H andZhao J 2019 Chlorotoxin peptide-functionalizedpolyethylenimine-entrapped gold nanoparticles for gliomaSPECT/CT imaging and radionuclide therapy. J.Nanobiotechnol. 17 30–44

Zheng D, Hong JC, Wang C and Zhu X 2019 Radiotherapytreatment planning in the age of AI: Are we readyyet? Technol. Cancer Res. Treat. 18 20–34

Corresponding editor: BJ RAO


radiopharmaceuticals: an insight into the latest advances

Documents