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ltered Biodistribution of Radiopharmaceuticals:ole of Radiochemical/Pharmaceuticalurity, Physiological, and Pharmacologic Factors

hankar Vallabhajosula, PhD, Ronan P. Killeen, MD, and Joseph R. Osborne, MD, PhD

One of the most common problems associated with radiopharmaceuticals is an unanticipatedor altered biodistribution, which can have a significant clinical impact on safety, scan interpre-tation, and diagnostic imaging accuracy. In their most extreme manifestations, unanticipatedimaging results may even compromise the utility and or accuracy of nuclear medicine studies.We present here an overall summary of altered biodistribution of radiopharmaceuticals with aspecial emphasis on the molecular mechanisms involved. Important factors affecting thebiodistribution of radiopharmaceuticals can be described in 5 major categories and include (1)radiopharmaceutical preparation and formulation problems; (2) problems caused by radiophar-maceutical administration techniques and procedures; (3) by changes in biochemical andpathophysiology; (4) previous medical procedures, such as surgery, radiation therapy anddialysis; and finally (5) by drug interactions. The altered biodistribution of 99mTc radiopharma-ceuticals are generally associated with increased amounts of 99mTc radiochemical impurities,such as free 99mTcO4

� and particulate impurities, such as 99mTc colloids or 99mTc-reducedhydrolyzed species. Faulty injection, such as dose infiltration or contamination with antisepticsand aluminum during dose administration, may cause significant artifacts. The patient’s ownmedical problems, such as abnormalities in the regulation of hormone levels; failure in thefunction of excretory organs and systems, such as hepatobiliary and genitourinary systems;and even simple conditions, such as excessive talking may contribute to altered biodistributionof radiopharmaceuticals. Previous medical procedures (chemotherapy, radiation therapy, dial-ysis) and drug interaction are the some of the nontechnical factors responsible for unantici-pated biodistribution of radiotracers. This review provides a comprehensive summary of variousfactors and specific examples to illustrate the significance of altered biodistribution ofradiopharmaceuticals.Semin Nucl Med 40:220-241 © 2010 Elsevier Inc. All rights reserved.

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uclear scintigraphy determined on the basis of radiophar-maceuticals has been practiced for more than 50 years. In

ecent years, designer radiopharmaceuticals or molecular imag-ng probes have been developed to image in vivo biochemical,hysiological, and pathologic processes by the use of positronmission tomography/computed tomography (PET/CT) andingle-photo emission computed tomography/computed to-ography (SPECT/CT) scanners. There are, however, several

epartment of Radiology, Weill Cornell Medical College of Cornell Univer-sity, Nuclear Medicine, STARR-221, New York, NY.

ddress reprint requests to Shankar Vallabhajosula, Professor of Radio-chemistry and Radiopharmacy, Department of Radiology, Weill CornellMedical College of Cornell University, 525 East 68th Street, NuclearMedicine, STARR-221, New York, NY 10065. E-mail: svallabh@med.

ncornell.edu

20 0001-2998/10/$-see front matter © 2010 Elsevier Inc. All rights reserved.doi:10.1053/j.semnuclmed.2010.02.004

roblems associated with the clinical use of traditional and mo-ecular imaging radiopharmaceuticals. The etiology of most ofhese problems can be classified into 4 major categories1 ashown in Table 1. One common result creates an unanticipatedr unusual imaging finding. Other common results go undetec-ed, particularly if they mimic pathology or mask underlyingisease. Not surprisingly, these cases can have a significant clin-

cal impact in safety, scan interpretation, and diagnostic imagingccuracy. In their most extreme manifestations, unanticipatedmaging results may even compromise the utility and or accu-acy of nuclear medicine studies. There are many factors bothxtraneous and in vivo that can alter the normal biodistributionf radiopharmaceuticals. It is important to recognize these fac-ors and to understand the specific mechanisms involved in theltered biodistribution to avoid both false-positive and false-
egative interpretation of scans. Over the years, several au-
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Altered biodistribution of radiopharmaceuticals 221

hors2-9 have reviewed extensively the various factors contribut-ng to the altered biodistribution of radiopharmaceuticals.

We present here an overall summary of altered biodistri-ution of radiopharmaceuticals with a special emphasis onhe molecular mechanisms involved. Several other articles inhe current and previous issues of the journal address theactors involved in the altered biodistribution of [18F]flu-rodeoxyglucose (FDG), radioiodide, and 99mTc radio-harmaceuticals.10-15 To understand the various factorsontributing to the altered biodistribution of radiophar-aceuticals, it is first important to understand the “tracerrinciple,” the specific mechanism(s) involved in the “nor-al” biodistribution of a radiopharmaceutical.

he “Tracer Principle”n the 1920s George de Hevesy coined the term radioindi-ator or radiotracer, which introduced the tracer principlen biomedical sciences.16 One of the most important char-cteristics of a tracer is the ability to study the componentsf a homeostatic system without disturbing their function.he term homeostasis is used by physiologists to mean

able 1 Classification of Problems Associated With Clinical U

nanticipated/unusualimaging results

Altered Biodistribution

Imaging artifacts

Normal anatomic variantsonsiderations for specialpatient populations

Considerations

Special populations

dverse reaction/untowardeffectsatient care, qualityassurance failures

Medication errorsMisadministration/recordableBlood handling/reinfusion errImproper preparation or exec

and therapeutic proceduresOther problems resulting in i

outcomes

aintenance of static, or constant, conditions in the inter- i

al environment by means of positive and negative feed-ack of information.A radiotracer can be defined as a specific radiolabeled mole-

ule (or probe) that resembles or traces the in vivo behavior of aatural molecule and can be used to provide information aboutspecific biological process.16 The degree of similarity between

adiotracer and the natural substance, however, may vary de-ending on the particular radiotracer. For example, [11C]glu-ose and [14C]glucose are “true” tracers of glucose because theyre chemically identical to natural glucose, whereas [18F]FDG isn analog of glucose that does not behave identically as it ishemically a different molecule. One of the most importantharacteristics of a true radiotracer, however, is the ability totudy the components of a homeostatic system without disturb-ng their function. Occasionally, the term radioligand is also usedn the context of imaging studies. Radioligand can be defined asny radiolabeled molecule that can bind with another moleculer substance (binder) in a predictable way under controlledonditions. For example, [11C]raclopride is a radioligand thatinds specifically to dopamine D2 receptors, whereas fluorine-8-L-dihydroxyphenylalanine ([18F]FDOPA) is a radiotracer to

Radiopharmaceuticals1

Radiopharmaceutical formulation problemsPathophysiologic interferenceConcomitant drug therapyLatrogenic traumaRadiation therapyBlood transfusionRenal/peritoneal dialysisInappropriate route of dose administrationSequencing artifactsOperator errorInstrumentation failurePatient-induced errorOther imaging artifacts

Radiation safetyDosimetryPatient preparationPregnancyBreastfeedingPediatricGeriatricDialysisIncontinent/catheterizedMiscellaneous

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222 S. Vallabhajosula, R.P. Killeen, and J.R. Osborne

adiopharmaceuticalhe terms, radiotracer, radioligand, and radiolabeled molec-lar imaging probe each have specific meaning depending onheir clinical context. From a regulatory point of view, theerm radiopharmaceutical represents any radiolabeled mole-ule intended for human use. All radiolabeled compounds orubstances used for diagnosis or therapy have been defined asadioactive drugs or radiopharmaceuticals by the US Food andrug Administration (FDA). From a regulatory point of view,owever, a radiopharmaceutical must also be sterile, pyrogenree, safe for human use, and efficacious for a specific indica-ion. In contrast, radiochemical is not an FDA-approvedgent for routine human use. It is important to remember thatiagnostic radiopharmaceuticals, however, are administered

n trace amounts (�100 �g), and typically, do not induce anyhysiological response or pharmacologic effect in patients.

actors Affectinghe Biodistribution ofadiopharmaceuticals

lthough several problems are associated with the clinicalse of radiopharmaceuticals (Table 1), important factors af-ecting the biodistribution of radiopharmaceuticals can beescribed in the following 5 major categories:

● factors associated with radiopharmaceutical preparationand formulation;

● factors caused by radiopharmaceutical administrationtechniques and procedures;

● factors caused by pathophysiological and biochemicalchanges;

● factors caused by medical procedures; and● factors associated with drug therapy or drug interaction

he physicochemical factors and molecular mechanisms in-olved in the altered biodistribution of radiopharmaceuticalsaused by the aforementioned factors will be described hereriefly with specific examples. To understand the basis and

able 2 Expected Biodistribution of Radiochemical Impurities

Radiopharmaceutical Factors9mTc agents Radiochemical (RC)

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11In agents RC impurities FrFr

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echanisms involved in the altered biodistribution, it is firstmportant to appreciate the quality control criteria and mech-nism(s) of radiopharmaceutical localization.

adiopharmaceuticals:uality Control Criteria

lthough alterations in the biodistribution of radiopharma-euticals may be related to several factors unrelated to theuality of radiopharmaceutical preparation, the purity anduality of a radiopharmaceutical preparation has a pro-ounced effect on the in vivo behavior of radiopharmaceuti-al, the subsequent scan interpretation, and the diagnosticccuracy of the imaging procedure.3,4

Before the administration of a radiopharmaceutical into auman subject, several quality control tests need to be per-ormed. These tests generally fall into 2 different categories;he physicochemical tests are essential to determine the,hemistry, purity, and the integrity of a formulation, whereashe biological tests establish the sterility and apyrogenicity ofhe radiopharmaceutical. Because the defects in radiophar-aceutical formulation are usually observed in the patient as

n altered biodistribution, following quality control testseed to be performed:

adionuclidic Purity (RP)t is defined as the fraction of total radioactivity present in theorm of desired radiopharmaceutical. RP depends on theuantities of desired radionuclide and other radionuclideontaminants, the relative half-lives of all the radionuclides,nd changes in the quantities of radionuclides with time. Theost common examples are 99Mo contaminant in 99mTc ra-iopharmaceuticals and 125I or 124I contaminants in 123I la-eled radiopharmaceuticals.

adiochemical Purityt is the fraction of the total radioactivity in the desired chem-cal form of a radiopharmaceutical. Several radiochemicalmpurities in a radiopharmaceutical formulation may formuring radiolabeling process (Table 2) or may arise because

diopharmaceuticals

Impurity Biodistribution

TcO4� Uptake in stomach, gastrointestinal

tract, thyroid, salivary glandscolloid,

(OH)n colloidPhagocytized by the cells of RES

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rticles (>10 �) Physically lodged in pulmonarycapillaries

ilic impurities Uptake in kidney and bladderic impurities Uptake in liver and GI tractlloids and particles Uptake in the lung and RES

In (111In-DTPA) Urinary excretion, bladder activityIn (as 111In-transferrinn-RBCs

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f decomposition as the result of unwanted chemical reac-ions or even because of radiolysis. Unacceptable amounts ofadiochemical impurities in a radiopharmaceutical preparationould result in altered biodistribution and poor image quality.he presence of free 99mTc pertechnetate (�5%-10%) in 99mTcadiopharmaceuticals and free radio iodide (�5%) in radioiodi-ated radiopharmaceuticals are the most common examples ofadiochemical impurities.

H and Ionic Strengthhe pH of a radiopharmaceutical intended for intravenousdministration ideally should be very close to the pH of blood�7.4). Significant change in pH, ionic strength, and osmo-ality of a radiopharmaceutical formulation may degrade then vitro stability and alter the subsequent in vivo behavior oriodistribution.

article Sizeertain radiopharmaceutical preparations may consist of ra-iolabeled particles in the form of particulate suspension.adiolabeled colloidal or macroaggregate particles shouldave a proper size range for a specific organ uptake or bio-istribution. For example, 99mTc-MAA particles (10-100 �)lock the capillaries in lungs, whereas 99mTc-sulfur colloidSC) particles (0.1-1.0 �) are taken up by Kupfer cells ineticuloendothelial system (RES) of liver, spleen, and bonearrow.

pecific Activityt is defined as the amount of radioactivity per unit mass of aadionuclide or radiolabeled molecule. Specific activity isenerally expressed as mCi/mg or mCi/�mol. Carrier is de-ned as the nonradioactive isotope of an element or a mole-ule. For example, with 99mTc radiopharmaceuticals, theresence of 99Tc (2.111 � 105 year) can be considered as aarrier, while in the case of 111In-pentetrotide (Octreoscan),he free diethylene triamine pentaacetic acid (DTPA)-oct-eotide precursor or the drug octreotide (Sandostatin) is re-arded as the carrier.

echanisms ofadiopharmaceutical Localizationadiopharmaceuticals can generally be classified on the basisf their unique mechanism of localization in a specific organ/issue of interest or based on their ability to image a specifichysiological and/or biochemical process. For example,

9mTc-MAA uptake in lungs is due to the blockade of capil-aries in lungs by MAA particles � 10 �. However, the lungcan obtained after intravenous administration of 99mTc-MAAan be used to assess pulmonary perfusion indirectly. In con-rast, FDG is a specific substrate for the enzyme hexokinaseecessary for glucose metabolism in vivo. The transport ofDG into cells is dependent on the number of glucose trans-orters (GLUT) and their subtypes on the cell membrane.he FDG-PET scan reflects altered glucose metabolism inifferent cell types and may, however, provide useful diag-ostic information to detect malignant tissue or simply even
ell viability. d
Various mechanisms involved in the localization of clini-ally useful and FDA-approved radiopharmaceuticals areummarized in Table 3. The localization of a radiopharma-eutical in a specific target organ or tissue of interest may,owever, depend on 3 important phenomena:

● Plasma protein binding, metabolism in blood, bloodclearance, and transport of radiopharmaceutical to thetarget organ or tissue of interest;

● Transport of radiopharmaceutical from capillaries intothe extracellular fluid and subsequent transport into thecells through cell membrane (transport processes, suchas simple diffusion, facilitated diffusion, active transportand receptor mediated endocytosis, do all play very im-portant role in the localization of the radiotracer at thetarget site); and

● Localization at the target site and intracellular trapping,which may be caused by any one of these followingbiochemical processes:X specific binding to receptors or on the cell membrane

or within the cell;X specific binding to extracellular or intracellular anti-

gens;X specific interaction with intracellular enzymes in-

volved in the intracellular metabolism; of radiophar-maceuticals and the subsequent trapping of metabo-lites; or

X incorporation into the biochemical synthesis of intra-cellular proteins or DNA.

nowledge of transport and intracellular localization mech-nisms of a given radiopharmaceutical is essential to under-tand various factors responsible for the altered biodistribu-ion of a radiopharmaceutical.

actors Associatedith Radiopharmaceuticalreparation and Formulation

n the basis of chemistry, various radiopharmaceuticals usedn nuclear medicine/molecular imaging can be grouped into

major categories.

● 99mTc radiopharmaceuticals;● Radiopharmaceuticals based on group III metals;● Radioiodinated radiopharmaceuticals; and● PET radiopharmaceuticals

brief description of chemistry, radiolabeling methods, andhe purity of radiopharmaceutical preparations are describedn the section to follow with special emphasis on the factorsontributing to the altered biodistribution.

9mTc Radiopharmaceuticalshe altered biodistribution of 99mTc radiopharmaceuticalsre generally associated with increased amounts of 99mTc ra-iochemical impurities (Table 3), such as free 99mTcO4

� andarticulate impurities, such as 99mTc colloids or 99mTc-re-
uced hydrolyzed species (99mTc-RH).9,17 In addition, to

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hese common 99mTc impurities, certain radiopharmaceuti-al preparations, such as 99mTc-hexamethylpropyleneaminexime (99mTc-HMPAO) and 99mTc-MAG3 may also containydrophilic or lipophilic impurities of the active ingredient,esulting in altered biodistribution.

actors Associated With 99mTc Generatorsarrier 99Tc. The decay of 99mTc results in rapid buildup ofarrier 99Tc and decrease in specific activity of 99mTc pertech-etate (TcO4

�) eluted from the generator. The amount of9Tc present in 99mTc pertechnetate eluate from a generator,herefore, depends on the time elapsed from the previouslution (Fig. 1). The 99mTc content in the eluate is generallyxpressed as a mole fraction (f) of 99mTc.9 For example, aenerator eluted only 3 hours after previous elution will con-ain mostly 99mTc atoms (73%). In contrast, a Monday morn-

able 3 Mechanism(s) of Localization of Radiopharmaceutica

Mechanism

sotope dilutionapillary blockadehagocytosisell migrationell sequestrationimple diffusioniffusion and mitochondrial binding

iffusion and intracellular binding

iffusion and increased capillary permeabilityacilitated diffusionctive transportNa�/I� sodium iodide symporter (NIS)Na�/K� ATPase pump

on exchange with hydroxyapatiteExchange with OH� ionExchange with Ca2� or calcium phosphate

lomerular filtrationubular secretionetabolic trappingGlucose metabolismTissue hypoxia and acidic pH

pecific receptor bindingHepatocyte anionic receptor

Somatostatin (SSTR2) receptorDopamine transporterNorepinephrine and serotonin transporters and

energy-dependent type I amine uptake mechanismntigen-antibody bindingCarcino embryonic antigenPSMACD20 antigen on B lymphocytes

CD20 antigen on B lymphocytes

ng elution (after 48 hours) will contain only a small fraction v

13%) of 99mTc atoms. Because 99Tc competes with 99mTc inabeling reactions, the total amount of 99Tc atoms affectshe labeling efficiency of 99mTc radiopharma-ceuticals, suchs 99mTc-labeled red blood cells (99mTc-RBCs), 99mTc-HMPAO,9mTc-DTPA, 99mTc-sulfur colloid (SC), 99mTc-MAG3, and9mTc-sestamibi. As a result, unacceptable levels of 99mTc per-echnetate impurity may be present in the final injected dose.

actors Associated With 99mTcabeling When Using Cold Kitshe 99mTcO4� ion with an oxidation state of 7� is chemicallytable, unreactive, and does not label any molecule directly.n most 99mTc kits, previous reduction of 99mTc from 7�xidation state to lower a lower oxidation state (such as 5� or�) is achieved by the use of stannous (Sn2�) chloride as aeducing agent. The reduced 99mTc species are chemically

Radiopharmaceutical99mTc-red blood cells (RBC)99mTc-macroaggregated albumin (MAA)99mTc-SC111In-oxine-white blood cells (WBC), 99mTc-HMPAO-WBCs99mTc-RBCs (heat damaged)133Xe gas, 99mTc-pertechnegas [15O]water99mTc-sestamibi (Cardiolite®)99mTc-tetrofosmin (Myoview®)99mTc-exametazine (HMPAO) (Ceretec®)99mTc-bicisate (ECD) (Neurolite®)99mTc-(DMSA)67Ga-citrate[18F]fluorodeoxyglucose (FDG)

123I and 131I sodium iodide (I�)201Tl-thallous chloride (Tl�)82Rb-chloride (RB�)[13N]ammonia as ammonium ion (NH4

�)

[18F]fluoride (F�)99mTc-medronate (MDP)99mTc-oxidronate (HDP)99mTc-pentetate (DTPA)99mTc-merteatide (MAG3)

[18F]fluorodeoxyglucose (FDG)67Ga-citrate

99mTc-disofenin, DISIDA (Hepatolite®)99mTc-mebrofenin (Choletec®)111In-pentetreotide (octreotide) (OctreoScan®)123I-ioflupane (DaTSCAN)123I and 131I-meta-iodobenzylguanidine (mIBG)

99mTc-arcitumomab (CEA-SCAN®)111In-capromab pendetide (ProstaScint®)111In-ibritumomab tiuxetan (111In-Zevalin®)90Y-ibritumomab tiuxetan (90Y-Zevalin®)131I-tositumomab (Bexxar®)

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ating agents, such as methylene diphosphate (MDP), DTPA,AG3, and sestamibi.Because the amount of 99mTc mass is very small (�10�9 M),

nly a small amount of Sn2� ion (�1.0 �g) are needed.owever, most 99mTc reagent kits contain large excess of

tannous chloride. The reducing capacity of Sn2�, however,s drastically reduced by a variety of factors, such as oxidationuring storage and kit preparation. Therefore, optimal Sn2�

evels in the reagent kits are essential to minimize 99mTc im-urities. Hydrolysis of excess stannous ion may result in theormation of 99mTc-stannous colloids, which subsequentlyre taken up by the RES.

eagent Concentration. Most 99mTc kits are prepared by these of 1 to 8 mL of 99mTc-pertechnetate solution. At greaterolumes, the reagent concentration decreases, and as a result,he labeling efficiency may decrease resulting in higher levelsf radiochemical impurities. It has been documented that inhe preparation of 99mTc-DMSA, 99mTc-iminodiacetic acidIDA) derivatives, and 99mTc-MAA, radiochemical impuritiesncrease with decreased reagent concentration.

actors Associated With Preparation Proceduresixing and Mixing Order. Optimal radiolabeling yields are

chieved when the different components of the reaction mix-ure in the vial are adequately mixed; sometimes even therder in which different components are added or mixed mayave a significant effect on the quality of the final formula-ion. In general, the chelating agent and the reducing agentstannous chloride) must be mixed before 99mTc-pertechne-ate is added to the reagent vial. If 99mTc interacts with Sn2� inhe absence of a chelating agent very high levels of 99mTc-tannous colloid impurity will be formed. The radiopharma-eutical preparations most affected by the mixing order are9mTc-sulfur colloid and 99mTc-RBCs (using Ultra Tag RBCit). Therefore, the procedure for the preparation of thesegents must be carefully followed as described in the package

igure 1 Mole fraction of 99mTc in 99mTc generator eluant at differentimes after elution.

nsert. I

ncubation. Although most 99mTc-chelates, such as 99mTc-DP and 99mTc-DTPA, are formed very rapidly, some com-

lexation reactions, such as 99mTc-MAG3 and 99mTc-sesta-ibi, require a substantial incubation time. Incubation times

f approximately 10 to 30 minutes may be required tochieve maximal labeling. Also, excessive incubation times orxcessive time delays between preparation steps can producendesirable effects. For example, inferior labeling of 99mTc-AG3 occurs if there is an excessive time delay (�5 min)

efore air is added or if there is an excessive time delay (�3in) between the addition of air and boiling.18

eating. Many 99mTc radiopharmaceutical preparations doequire heating to accelerate the kinetics of chemical reac-ion. Insufficient or over heating may lead to poor radiolabel-ng or formation of radiochemical impurities. Several factors,uch as temperature and duration of heating mixture, mayffect the quality of the final product. In addition, heating ofmall volumes is more uniform and efficient than heating ofarge volumes. The preparation of 99mTc-SC, 99mTc-MAG3,nd 99mTc-sestamibi, heating under optimal conditions asescribed in the package insert are essential to avoid forma-ion of radiochemical impurities. For example, in the prepa-ation of 99mTc-SC, the reaction of HCl with sodium thiosul-ate (Na2S2O3) is optimal at 95 to 100°C for 5 minutes. If theixture is heated for an insufficient period, poor liver and

plenic uptake can result; if it is heated for an extended pe-iod, lung uptake of large “colloidal” particles may result.19

he chemical form and/or nature of a radiopharmaceuticalay change during the incubation period, with resultant al-

eration in biodistribution. For example, bone-to-soft tissueatios for 99mTc-MDP are reportedly greater after a 30- to0-minute incubation period than after shorter incubationimes, although the percentage labeling efficiency remainsnchanged.20 Similarly, when 99mTc-DTPA is used to deter-ine glomerular filtration rate (GFR), it is recommended that

he preparation is used within 1 hour of preparation; how-ver, it has been observed that protein binding of 99mTc-TPA to human serum albumin actually decreases over time,

uggesting a radiochemical impurity that is minimized after0 to 90 minutes of incubation.21

actors Associated With In Vitro Stability9mTc radiopharmaceuticals are generally stable for severalours (up to 8 h). Following radiolabeling, the stability of

9mTc radiopharmaceutical, may be affected by several fac-ors.22,23 For example, even large volume of 99mTc-DTPA and9mTc bone agents may deteriorate due to generation of free9mTc pertechnetate.

xidation/Reduction Reactions and Radiolysis. Also, oxi-ation caused by soluble oxygen, hydrogen peroxide (H2O2),r hydroperoxy free radicals (� HO2) and even radiolyticecomposition, may all lead to increased levels of 99mTc-ertechnetate and/or 99mTc-colloid impurities. The radiolyticroduction of oxidizing agents in 99mTc-pertechnetate solu-ions is a contributing factor in the poor labeling efficiencynd stability of 99mTc-HMPAO prepared with aged eluates.24

n contrast, purposeful addition of oxidizing agents may be

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equired to produce a high labeling yield. For example, ateast 2 mL of air must be added during the preparation of9mTc-MAG3 to prevent the progressive formation of radio-hemical impurities.18 Similarly, oxygen bubbling will con-ert 99mTc-DMSA (trivalent complex), the traditional renalortex agent, into 99mTc-DMSA (pentavalent) complex, a tu-or-imaging agent.25 Some radiopharmaceuticals are also

ulnerable to chemical decomposition; for instance, hydro-ysis of 99mTc-ECD after radiolabeling can lead to formation ofts monoacid monoester product, which does not cross thelood–brain barrier.26

Hydrogen ion concentrations have a dramatic impact on

onic equilibria, solubility, and oxidation/reduction reac-ions. Therefore, it is not surprising that pH affects the sta-ility and purity of many radiopharmaceuticals. Significantlterations in pH of the labeling media can have markedffects on the radiochemical purity and/or stability of many9mTc-labeled radiopharmaceuticals. Sn2� solutions becomensoluble and form colloidal precipitates at neutral and alka-ine pH. With 99mTc bone agents, acidic pH formulations aredeal, but at neutral and alkaline formulations, poor boneffinity and kidney localization have been observed. Differentadiolabeled complexes with significant differences in biodis-ribution have also been reported with 99mTc-DMSA and9mTc-IDA formulations.3 The stability of some radiopharma-euticals is affected by pH. For example, 99mTc-sulfur colloid,9mTc-HMPAO and 99mTc-MAG3 may decompose at pH val-es � 7.0 and form radiochemical impurities.3

ole of Aluminum Ion (Al3�) Contaminationhe interaction of Al3� with several 99mTc radiopharmaceu-

icals is known to alter their biodistribution. The source ofl3� is either breakthrough from the alumina column used in

he 99mTc generator or because of leaching from aluminum-ub needles. The Al3� from the generators may not be a

Figure 2 Altered biodistribution of 99mTc-MDP bone sccaused by free 99mTc pertechnetate. (B) Diffuse liver uptaonline.)

roblem with the current generators, but the leakage from t

yringe needles depends on pH and other factors. Even atery low concentrations (1.0 �g/mL), Al3� reacts with phos-hate buffer and forms insoluble aluminum phosphate.27

9mTc-SC coprecipitates with aluminum phosphate and theocculated particles are trapped in the lung capillaries.3 Atigher concentrations (�10 �g/mL), Al3� may react with

9mTc-MDP forming insoluble particles, which are taken upy the cells of RES in liver (Fig. 2) and spleen.28 Alterediodistribution in the presence of excess Al3� was also ob-erved with 99mTc pertechnetate and 99mTc-DTPA.3

adiopharmaceuticalsetermined on the Basis of Group IIIa Metals

he 3 important metals (M) in group IIIa (or group 13) areallium (Ga), indium (In), and thallium (Tl). These 3 metalsre posttransition metals and have 3 electrons in the outerost shell. In contrast, yttrium (y), a transition metal has an

ncomplete d shell with 1 electron and 2 electrons in theutermost shell.The aqueous chemistry of these metals is dominated by

heir ability to form strong complexes (both soluble and in-oluble) with the hydroxyl ion. At neutral pH, Tl predomi-antly exists as a mono cation, Tl(OH)2

�, and as a result,01Tl (as thallous chloride) is considered to behave similarlyo potassium with respect to biochemistry and physiology.

In contrast, with Ga, in and Y, the fully hydrated M3� ionsre only stable under acidic conditions. Their coordinationhemistry is somewhat similar and the most important oxi-ation state is MIII. As the pH is raised above 3, these metalsorm insoluble hydroxides (M(OH)3) and the total solubilityt physiological pH is very limited. Very high SA of radiom-tals is needed to keep them soluble in water. However, it iscommon practice to add weak chelating agents (such as

itrate, acetate or tartrate ion) to complex the metal and pre-ent precipitation at neutral pH. For example, 67Ga is used in

sed by radiochemical impurities. (A) Thyroid uptakeed by 99mTc colloids. (Color version of figure is available

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he clinic as 67Ga-citrate. These 3 metals also share chemical

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haracteristics with the ferric ion (Fe3�). This similarity witherric ion is important in the development of radiopharma-euticals because iron is an essential element in the humanody and many iron binding proteins, such as transferrin inlood, do exist to transport and store iron in vivo. As a result,he atoms of iron always compete with these radiometals inivo for specific binding with proteins, such as transferrin,actoferrin, and ferritin.29 For example, following intrave-ous administration of 67Ga-citrate, 67Ga, binds to transferrin

n plasma and transported to tumor and infectious foci asGa-transferrin complex.”30 Several important radiopharma-eutical, preparation/formulation pitfalls, and artifacts asso-iated with radiometals do generate radiochemical impuritiesesponsible for the altered biodistribution.

actors Associated With the Radionuclidepecific Activity and Carrier. For the cyclotron producedadiometals (67Ga,111 In, 201 Tl), the SA is very high and gen-rally available as no-carrier-added (n.c.a) form, whicheans that the radiometal is produced without any addition

f stable isotopes of the same element (specific carrier) in theystem. The presence of excessive carrier in the 67Ga citrateeads to a dramatic change in biodistribution, and 67Ga be-omes a bone-seeking agent.31,32

In labeling reactions, the presence of carrier decreases thencorporation rate of the radionuclide and therefore the SA ofhe radiopharmaceutical. The same effect arises by the pres-nce of unspecific carriers, namely other metallic cations inhe system. They can be either stable decay products of theadionuclide or external chemical impurities. Thus, di- andrivalent metals, such as Cu, Zn, Fe, and Ln, even at micro-ram levels were found to be strong competitors in the radio-abeling reactions.33

ommercial Source. There may be significant differences inhe purity and formulation of radiometals supplied as radio-harmaceuticals or as radiochemicals for labeling reactions.n 1970s, different sources of 67Ga-citrate were implicated inifferent localization characteristics in cerebral infarcts.he 111InC13 supplied with the octreotide kit and the

11InC13 specified for antibody labeling are not inter-hangeable. They differ in many ways, including buffer,H, and trace metal ion concentrations, all of which canffect labeling yields and radiochemical purity.

actors Associated With Preparation Proceduresixing Order and Incubation. In the preparation radiola-

eled peptides and antibodies with 111In and 90Y, the order ofixing is very important. As described previously, 111In chlo-

ide and 90Y chloride hydrolyze at neutral pH and thereforere supplied in dilute hydrochloric acid. In the absence of aolubilizing ligand, such as citrate, the metal hydroxide willrecipitate. The kits for the preparation of Octreoscan, Pros-aScint, and Zevalin® include 3 components: 111InCl3, ace-ate buffer, and the peptide or antibody. It is imperative thathe directed amount of buffer be mixed with the 111InCl3efore it is mixed with the peptide or antibody. Failure to
ollow this order of mixing and use the correct volume of (
uffer results in inadequate yields and radiochemical impu-ities, such as colloids (Table 2).

Most reactions involving chelating agents require an opti-al incubation time (20-60 min) and temperature (25-

5°C). For example, labeling of WBCs with 111In or 99mTcequires an incubation time of at least 20 to 30 minutes.owever, prolonged incubation and/or delay in reinjection

�3 hours) leads to significantly decreased viability ofeukocytes.

ngredients of the Incubating Medium. The presence oflasma transferrin reduces labeling yields for WBCs because

t complexes 111In much more avidly than does oxine.34 With11In, the presence of transferrin or increased RBC contami-ation in the incubation mixture will cause binding to trans-errin and RBCs and shows very high blood pool activity andncreased uptake in spleen. It has been documented that ifaline is used to rinse out the 111In vial when DTPA-oct-eotide is labeled, radiochemical purity decreases due to traceetal ions in the saline. For 111In-oxine-labeled WBCs, ACD

olution is preferred as an anticoagulant because it decreaseshe adherence of neutrophils to the walls of the vessel andipettes.35

tability. Radiolytic generation of free radicals is a majoractor responsible for degradation of radiolabeled prepara-ion. Radiolytic decomposition, especially of disulfide bondsn the peptide molecule, decreases the stability and purity ofctreoscan. Similarly, the stability of 111In and, especially

0Y-labeled antibodies decreases with time and with increas-ng temperature. One of the potential problems with mono-lonal antibody preparations is the precipitation of dena-ured protein particles, which will localize in the lung, liver,nd/or spleen depending on their size. Similarly clumpingnd/or cellular damage of radiolabeled WBCs results in lung,iver, and/or spleen uptake. Radiolabeled proteins must beept frozen to minimize the radiolysis effects. With 111In-BCs, if the handling and storage are done in saline instead

f plasma, viability of labeled leukocytes decreases. A lowerensitivity for abscess detection was reported when the la-eled cells were stored in saline for more than 1 hour.3

luminum Ions. Al3� ions from aluminum hub needles maylso have a significant effect on 111In labeling reactions. Forxample, decreased labeling yields and purity with 111In-entetreotide (Octreotide®) have been observed. That ishy a stainless-steel needle is supplied with the kit. 111In-xine may from a cloudy precipitate by reaction with Al3� ioneached from the glass vials and tubes of some suppliers’ vials.s a result, 111In-WBC preparation may have unacceptable

evels of radiochemical impurities, such as colloids and cellrecipitates.

H. As discussed earlier, pH has a dramatic impact on ionicquilibria and solubility of radiometals. The oxidation statef 201Tl ions is strongly influenced by pH. An alkaline pHavors the formation of the desired thallous ions (Tl(OH)2

�),hereas a low acidic pH favors the formation of thallic ions

Tl3�), which may form complex ions that give thyroid and

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BCs uptake and/or hydrated colloids that are phagocyti-ed by the RES.36 In the preparation of OctreoScan® androstaScint®, the reagent kits contain citrate and acetateuffers, respectively, which help raise and maintain the pH athe optimum levels (pH 5-6) for improved labeling and sta-ility of the carrier molecule, but also prevent hydrolysis of

11In ions.

pecific Activity. SA is an important quality control param-ter for target specific radiopharmaceuticals and the effects ofecreased SA on biodistribution are most pronounced whenhe mechanism for localization of the agent shows saturationharmacokinetics. Whenever a limited number of receptorites, carriers, enzymes, or antigens are responsible for theocalization, the carrier (the unlabeled molecule) will com-ete with the specific radiopharmaceutical for these limitedites; if saturation occurs, target-to-background radioactivityatios will decrease.

adioiodinated Radiopharmaceuticalsodine belongs to Group 7-A elements (halogens) and is char-cterized by the presence of 2 s electrons and 5 p electrons inhe outer most valence shell (5s2 5p5). Among the radioiso-opes of iodine, 123I, 124I, and 131I have suitable physical char-cteristics for developing radiopharmaceuticals. Besides 131Is sodium iodide, 2 other important radiopharmaceuticalssed for therapy are 131I-Bexxar® and 131I-mIBG. 123I as so-ium iodide and several 123I labeled investigational radio-harmaceuticals are used for imaging studies.A total of 15 to 20 mg of iodine is concentrated in thyroid

issue and hormones, but 70% of the body’s iodine is distrib-ted in other tissues, including mammary glands, eyes, gas-ric mucosa, the cervix, and salivary glands. In the cells ofhese tissues, iodide enters directly by Na�/I� symporter.37

he thyroid gland needs no more than 70 �g/d to synthesizehe requisite daily amounts of T4 and T3, but the averageaily dose is 150 to 300 �g. The US Food and Nutritionoard and Institute of Medicine recommended daily allow-nce of iodine ranges from 150 �g/d for adult humans to 290g/d for lactating mothers.The free molecular iodine (I2) has the structure of I��I� in

queous solution. However, the electrophilic species (I�)oes not exist as a free species but forms complexes withucleophilic entities, such as water or pyridine. The hydrated

odonium ion, H2OI� and the hypoiodous acid, HOI, areelieved to be the highly reactive electrophilic species. In an

odination reaction, iodination occurs by (1) electrophilicubstitution of hydrogen ion by an iodonium ion in a mole-ule of interest or (2) nucleophilic substitution (isotope ex-hange) where a radioactive iodine atom is exchanges with atable iodine atom that is already present in the molecule.9

Several important factors that affect the altered biodistri-ution of radio iodide and radioiodinated radiopharmaceu-icals are briefly discussed here. Anatomic and physiologicalariants in radioiodine studies are discussed in greater detail
n this issue.14 a
arrier. The dietary iodide, 127I (carrier), and iodine-con-aining drugs alter the normal biodistribution and depresshe uptake, especially by the thyroid gland. As little as 1.0 mgf stable iodide decreases the 24-hour uptake, and �10 mgirtually blocks the thyroid uptake of radio iodide.38 Theolatility of 131I from therapeutic sodium iodide solutionsncreases at higher total iodide (radioactive � stable iodide)oncentrations.39

adionuclidic Impurities. The contamination of other radio-sopes of iodine in 123I sodium iodide capsules or liquis for-

ulation depends on the nuclear reaction used for the pro-uction of 123I in a cyclotron. 124I (�� emitter, T½ � 100.8ours) and 125I (T½ � 60 days) are the major radionuclidic

mpurities. Significant image degradation may be caused byompton scatter and septal penetration from high-energyhotons emitted by 124I.

ommercial Source. Differences have been reported for theissolution and bioavailability of radioiodine capsules.40 131I-odium iodide capsules from different sources have shownifferences in thyroid uptake when compared with uptakeeasurements performed with liquid 131I preparation.41

adiolysis and Stability. Radiolytic generation of free radi-als is a problem with 131I because it emits high-linear energyransfer radiation. High specific concentrations and the highinear energy transfer of the particulate radiations result in

high level of free radical production and radiolysis. Inadiopharmaceutical formulations of 131I-mIBG and 131I-exxar®, radiolysis generates radiochemical impurities, suchs free 131I iodide.42 In case of 131I-Bexaar®, radiolysis mayecrease the immunoreactivity of labeled monoclonal anti-odies. To prevent the effects of radiolysis, 131I-Bexxar® isupplied frozen and is safe for use when it is kept frozen (at20°C) for several days.

olatility. The production of volatile airborne iodine occurss the result of the oxidation of iodide by dissolved oxygen inlightly acidic solution. The use of buffers to increase the pHo alkaline levels or addition of reducing agents (sodiumisulfite or thiosulfate) will significantly lower the rate ofolatility. Inhalation of gaseous iodine is a potential radiationafety problem and there may be significant radiation expo-ures to the thyroid glands of occupational workers.

adiopharmaceuticals for PEThe 4 radiopharmaceuticals approved by FDA for routinelinical studies43 are FDG, [18F]fluoride, [13N]AmmoniaNH4

� ion), and 82Rb-chloride (RB�). Because FDG is thenly PET radiopharmaceutical widely used, some of the im-ortant factors responsible for the altered biodistribution areiscussed in the sections to follow.

DG and Fluoridemong the halogens, fluoride ion (F�) is more stable than

odide because fluorine is the most electronegative element
nd has only 1 oxidation state (�1). When a water (H2
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actors Cause byadiopharmaceuticaldministration

echniques and Proceduresaulty Injection Techniquenfiltrated Injection. Most defects related to radiopharma-eutical administration are the result of extravascular or in-ltrated activity at the injection site (Fig. 3).3 When signifi-ant subcutaneous extravasation occurs in the antecubitalegion, regional lymph nodes can be visualized as the infil-rated radiopharmaceutical is partially cleared through theymph vessels.5 These defects, however, should not be mis-aken for loci of abnormal uptake. For example, infiltration of9mTc-MDP showed focal axillary uptake ipsilateral to thenjection site.44

A potential harmful effect of extravascular injection is theadiation “burn” caused by the significant amount of localbsorbed radiation dose from the infiltrated radionuclide,3

specially if decays by pure �� emission (eg, 131I or 90Y) orlectron capture (eg, 201Tl, 111In or 67Ga). Maximum radiationose to the tissue, however, depends on the nuclide, activitynd volume of infiltrated dose.45 For example, infiltration of4 MBq of 201Tl may deliver up to 200 Gy (20,000 rads)

igure 3 Bilateral lymphoscintigrapy with 99mTc-SC: One of the in-ections infiltrated the venous system causing reticuloendothelialptake generally seen in a liver-spleen scan. (Color version of figure

es available online.)

adiation dose to the local tissue.46 Specific corrective actionssuch as local heat, massage, and steroid application) fornfiltrated radiopharmaceuticals are recommended.3

ormation of Blood Clots in the Syringe. While radiophar-aceuticals are being injected intravenously, during backithdrawal of unanticoagulated blood into the syringe, blood

lots may form.3 The radiopharmaceutical could then bind tolots and localize in the lung.47 Such focal “hot spots” in lungsFig. 4) have been observed following administration of9mTc-MAA and 99mTc-albumin colloid.

ang Up of Activity in Administration Lines. If the patientas difficult veins to access, central line or porta catheter

njection of radiopharmaceuticals usually is required. Fol-owing administration of the radiopharmaceutical, if the lines not entirely flushed with physiological saline to remove anyesidual activity in the line, imaging artifacts may show up asocal or tubular activity because of the hang-up of activity athe tip or in the tubing. The administration of 99mTc radio-harmaceuticals via heparinized catheters may also producertifacts. 99mTc may bind to heparin and the 99mTc-heparinomplex may localize avidly in the kidneys.3

atient Position During Radiopharmaceutical Administra-ion. Decreased activity in the upper lobes of the lung per-usion scan (Fig. 5) with the use of either 99mTc-MAA or9mTc-DTPA radioaerosol has been observed when the pa-ient was sitting at the time of dose administration.48

ontamination of RP With Swab Antiseptic or Componentsf a Syringe. If an antiseptic used to swab the vial is notllowed to dry completely on the septum, the antiseptic may

igure 4 Lung scan showing blood clots. During intravenous admin-stration of 99mTc-MAA, blood was first withdrawn into the syringend labeled clots were subsequently reinjected.

nter the vial when the syringe needle punctures the septum.

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he antiseptic may interact with the radiopharmaceuticalnd produce radiochemical impurities (Fig. 6). The antisep-ic proviodine has been reported to inhibit the 99mTc-SC la-eling reaction and cause increase of free pertechnetate for-ation.49 Chlohexidine was reported to have produced 99mTc

olloid complex during 99mTc-DMSA preparation, and maylso have caused aggregates in 99mTc-SC preparation.3 Also,sopropyl alcohol was known to cause the breakdown of9mTc-hydroxymethylene diphosphonate (HDP) into free9mTc pertechnetate.50

actors Caused byathophysiologicalnd Biochemical Changesltered biodistribution of a radiopharmaceutical may some-

imes be the result of unanticipated or atypical pathophysio-ogic and biochemical mechanisms often beyond those forhich the study was originally indicated. A patient’s ownedical problems, such as abnormalities in the regulation oformone levels; failure in the function of excretory organsnd systems, such as hepatobiliary and genitourinary sys-ems; and even simple conditions, such as excessive talking,xercise, and restlessness, may all contribute to the unex-ected alterations in the biodistribution of radiopharmaceu-icals. As discussed previously, an understanding of theormal pharmacokinetics, biodistribution, and mecha-isms of radiopharmaceutical localization is very impor-ant to determine the pathophysiological basis for the al-ered biodistribution. Some of these factors as they are

igure 5 Lung perfusion scan with 99mTc-MAA. (A) Hypoperfusionf upper lobes when the patient was sitting at the time of injection.B) Repeat scan on the next day shows normal perfusion while theatient was supine during the injection.

igure 6 Kidney scan with 99mTc-DMSA contaminated with a bacte-
bicide. The images show abnormal uptake in liver and spleen.
ertinent to specific radiopharmaceuticals are discussed inhe sections to follow.

one Scanhe main mechanism of bone uptake of 99mTc agents and

18F]fluoride is by ion exchange or chemisorption onto boneurface. The bone crystal, hydroxyapatite, Ca10(PO4)6(OH)2,as a surface composed of many different ions, includingonovalent, divalent, and trivalent species of both positive

nd negative charge. 99mTc agents (MDP and HDP) appear toocalize by cationic substitution for calcium ions. In contrast,18F]fluoride ions localize by anionic substitution for the hy-roxyl ions (OH�) forming fluoroapatite. The favorableroperties of bone agents include their rapid clearance fromlasma and high urinary excretion, which contribute to theigh contrast between bone and soft tissue. Plasma proteininding may be significant (25%-55%) with 99mTc agents,hereas plasma protein binding of fluoride is negligibly

mall, and fluoride ions are freely filtered by the glomerulus.n general, uptake of [18F] fluoride and 99mTc agents in bone,epend on local blood flow, osteoblastic activity and extrac-ion efficiency. The bone uptake of fluoride was reported inoth sclerotic and lytic lesions, while the uptake of 99mTc-DP in lytic lesions is relatively insignificant.Extraosseous uptake of 99mTc agents has been observed in

everal soft tissues, such as breasts, lungs, muscle, liver, cal-ified arteries and kidney.11,51-53 In general the mechanismsf uptake in soft tissue are reported to be similar to those for

igure 7 Altered biodistribution in 99mTc-MDP bone scans. (A) As theesult of chronic renal failure, a peritoneal dialysis catheter and poorony localization is seen. (B) As the result of acute renal insufficiencyrom chemotherapy-induced acute tubular necrosis, intense renal up-ake is seen. (Color version of figure is available online.)

ones.11,51 Urinary contamination is a common problem,

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hich may simulate focal lesions, especially if close to orverlying the bone. Increased muscle uptake and poor con-rast as the result of renal failure (Fig. 7) may degrade imageuality significantly. “Super scan” appearance on bone scanFig. 8) as the result of hypercalcemia shows intense skullptake with a paucity of excretory activity, posterior rib frac-ures and subperiostial resorbtion at the synphesis pubis, allndicating altered biodistribution.

lucose Metabolismhe transport of glucose into cells is mainly through facili-

ated diffusion, also called carrier-mediated diffusion, becausehe carrier facilitates the transport of glucose into the cell.nsulin can increase the rate of facilitated diffusion 10- to0-fold. Six isoforms of GLUT have been identified, whichiffer in kinetic properties, tissue location, etc. It has beenhown that the overexpression of GLUT-1, GLUT-3, andLUT-5 play a major role in increased transport of glucose by

umor cells. Glucose may also be transported into the cell byctive transport, which mostly occurs in renal tubules andastrointestinal membrane. As a glucose analogue, [18F]FDGnters the cell membrane by using the same transporters aslucose. It is then phosphorylated into [18F]FDG-6-phos-hate. This metabolite is not a substrate for further enzymesnd thus is trapped and accumulates inside the cell in pro-ortion to the metabolism of glucose.16 Although many tis-ues and cells accumulate FDG to a predictable extent, for

igure 8 99mTc-MDP “superscan” caused by hypercalcemia. Intensekull uptake with a paucity of excretory activity, posterior rib frac-ures and subperiostial resorbtion at the symphesis pubis are alllues. (Color version of figure is available online.)

xample, the brain typically shows intense uptake of FDG, f

hereas myocardial uptake is intense in patients who haveot fasted but highly variable in patients who have fasted,dipose tissue typically shows minimal FDG uptake. How-ver, certain adipose deposits (so-called “brown fat”) can beramatically activated in a cold or nervous patient.12

Although many tissues and cells accumulate FDG to aredictable extent, for example, the brain typically shows

ntense uptake of FDG, whereas myocardial uptake is intensen patients who have not fasted but highly variable in patientsho have fasted, the glycolytic activity of a given tumor isenerally assumed to be characteristic of its state of differen-iation. The extent of FDG uptake in tumors, especially un-reated tumors, appears to relate directly to the number ofiable cells. Inflammatory cells, especially macrophages, canometimes accumulate FDG to a considerable extent, so in-ammatory or infectious sites are sometimes visualized onET. Adipose tissue typically shows minimal FDG uptake,ut certain adipose deposits (so-called “brown fat”) can beramatically activated in a cold or nervous patient.54

One of the important factors making FDG-PET scan diffi-ult to interpret is variable physiological uptake of FDG byormal tissues.13,54-58 Altered biodistribution of FDG related

s mainly because of hyperglycemia or hyperinsulinemia andone marrow activation commonly encountered in canceratients. Unlike glucose, FDG is not well reabsorbed by theroximal tubules of the kidney. Thus, it can be predicted that

ntense activity will be seen in the kidneys and bladder. How-

igure 9 Effect of sudden increase in insulin levels on FDG-PET. Inpatient undergoing staging of lymphoma, the FDG-PET scan (A)as performed after the patient had eaten a candy bar 30 minutesefore FDG injection. Note the extensive myocardial and muscleptake caused by high insulin levels. Diminished activity is seen inhe brain and in tumor sites in the neck and chest (arrows). A repeattudy (B) after the patient complied with routine fasting shows moreormal biodistribution of tracer and better visualization of tumor
oci (arrows).

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ver, focal pooling of excreted activity in a ureter could beonfused with a hypermetabolic iliac lymph node metastasis.yperglycemia and hyperinsulinemia are very important

onsiderations when preparing a patient for a PET study withDG. Acute hyperglycemia is a well-documented factor thateduces FDG uptake by the tumor tissue and augments mus-ular uptake but this effect has mostly been demonstratedith glucose-loading studies.59 High levels of insulin willush FDG, along with glucose, into skeletal muscle and myo-ardium, increasing the image background and decreasinghe availability of the tracer for uptake by the tumor.60 Fast-ng is essential for the quality of the FDG-PET scan: alteredracer biodistribution caused by ingestion of even a smalleal (Fig. 9) shortly before a FDG injection can impair the

isualization of malignant lesions. In premenopausal women,ncreased ovarian or endometrial FDG uptake can be func-ional or malignant. Benign functional uptake of ovaries orterus is related to the menstrual cycle.61

yocardial Perfusion Imagingeveral SPECT and PET radiopharmaceuticals are availableor imaging the relative myocardial perfusion or blood flow.he ideal flow tracer accumulates in or clears from myocar-ium proportionally linear to myocardial blood flow (MBF).he relationship between uptake and clearance of the radio-

racer and MBF should be constant and independent of MBF,f physiological and pathologic changes of myocardial tissuetate, and myocardial metabolism. Most radiotracers used formaging myocardial perfusion/blood flow, however, do notully meet these requirements.62

The PET tracers, [13N]Ammonia (NH3) and 82Rb� (as a K�

nalog) are actively transported into myocardial cells viaa�/K� pump. The lipid soluble ammonia may also be trans-orted into the myocardial cells by passive diffusion. Insidehe cell, ammonia is quickly converted to ammonium ionhich is rapidly converted and trapped as glutamine by the

nzyme glutamine synthase.62

201Tl (thallous chloride) at pH 4-7 predominantly exists asmono cation, Tl(OH)2

�, and like K� ion, it relies on cellembrane integrity and active metabolic transport usinga�/K� pump for its uptake into myocardial cells. After ini-

ial localization, however, there is rapid redistribution of 201Tlctivity in the myocardium. In contrast, the 99mTc agent (car-iolite® or Myoview®) as a cationic complex, is transported

nto the myocardium by passive diffusion.63,64 The subse-uent myocardial retention is mainly due to mitochondialinding. Because tumor cells have a greater mitochondrialensity than the surrounding epithelial cells, 99mTc-sestamibilso accumulates more avidly in tumor cells.64

The uptake and clearance kinetics of myocardial perfusionadiotracers, especially from liver and kidney, establish theracer levels in the circulating blood, which in turn affects theyocardial tracer kinetics. Tracer activity in lungs and liver

omplicates imaging of the heart. The biodistribution of theseracers may also be affected by the level of exercise or the type
f pharmacologic stress.63 w
adio Iodide Scanodium iodide (123I and 131I) is readily absorbed from theastrointestinal tract. After absorption, the iodide is distrib-ted primarily within the extracellular fluid of the body. It isoncentrated and organified by the thyroid and trapped butot organified by the stomach and salivary glands. It is alsoromptly excreted by the kidneys. Stimulation of radioiodideptake by the thyroid may be achieved by the administrationf thyrotropin. Radioiodide will not be taken up by giant cellnd spindle cell carcinoma of the thyroid nor by the amyloidolid carcinomas. The uptake of radio iodide will be affectedy recent intake of stable iodine in any form, or by the use ofhyroid, antithyroid, and certain other drugs. Accordingly,he patient should be questioned carefully regarding previ-us medication and procedures involving radiographic con-rast media. A phenomenon known as thyroid stunning haseen described in which a diagnostic dose (2-10 mCi) of 131Iodium iodide decreases uptake of a subsequent therapeuticose by remnant thyroid tissue or functioning metastases.hether stunning is a temporary phenomenon whereby

tunned tissue eventually rejuvenates, or whether observedtunning actually constitutes “partial ablation,” is yet to beelineated.65 Radioiodine is excreted in human milk during

actation.Several potentially misleading artifacts can arise from con-

amination by physiological or pathologic secretions derivedrom those organs that are capable of uptake and excretion ofadioiodine (Table 3). These include urine, saliva, nasal secre-ions, other respiratory tract secretions, sweat, vomit, and breastilk (Fig. 10). False-positive radioiodine scans in thyroid cancer

ttributable to anatomic and physiological variants, such as1) contamination by physiological secretions, (2) abnormalitiesf gastrointestinal uptake, (3) urinary tract abnormalities,4) mammary uptake, (5) uptake in serous cavities and cystspleural, peritoneal, and pericardial effusions), (6) sites of infec-ion/inflammation, and (7) nonthyroidal neoplasms have beenxtensively reviewed previously.66,67

igure 10 Diagnostic scan with of 131I sodium iodide, 37 MBq, inatients after thyroidectomy. (A) normal biodistribution showingtomach and GI activity. (B) Abnormal breast uptake in a patient 1
eek after weaning after 18 months of lactation.

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nfection/Inflammationnflammation is a complex tissue reaction to injury, specifi-ally caused by or involves living microbes. Acute inflamma-ion is the early or an immediate response to injury and isssociated with many regional and systemic changes, such asasodilation and increased vascular permeability. Several in-ammatory cells, particularly polymorphonuclear leuko-ytes accumulate and aggregate at the site of inflammation.

hen the inflammation progresses to a chronic stage, thenflammatory cells are predominantly lymphocytes, plasmaells and fibroblasts. The two important radiopharmaceuti-als routinely used for imaging infection/inflammation areeukocytes (WBCs) labeled with 111In-xine or 99mTc-HMPAOCeretec®) and 67Ga-citrate.68 The radiolabeled cell prepara-ions are the only target specific radiopharmaceutical localiz-ng at the site of acute inflammation caused by cellular mi-ration.

67Ga-citrate is a nonspecific agent and the localization athe sites of inflammation is mostly due to the leakage of7Ga-transferrin complex from blood into the extracellularuid space of the inflamed tissue. The acidic pH at the site of

nfection, favors dissociation of 67 Ga from transferrin withubsequent 67Ga binding to other iron-binding proteins,uch as lactoferrin in the extracellular fluid or within thenflammatory cells. Because tracer amounts of 67Ga adminis-ered dose (�50 ng) is bound to transferrin, any physiolog-cal and pathologic conditions decreasing the iron bindingapacity of transferrin (such as iron-overload), would signif-cantly alter the biodistribution of 67Ga-citrate.

eceptor Imaginghe term receptor is generally used to denote a specific cel-

ular binding site for a small ligand, such as peptide hor-ones and neurotransmitters. Because the mechanism of

ocalization of receptor binding radiopharmaceuticals is spe-ific and depends on receptor expression on target cells, mul-iple factors representing many characteristics of the radio-harmaceutical will influence the uptake of radiotracer in the

igure 11 111In-Octreoscan (A) and axial CT lung window imagesB). Unusual lung uptake of 111In activity due to diffuse inflamma-ory processes (pulmonary interstitial fibrosis). (Color version ofgure is available online.)

arget tissue, image quality, and ultimately the clinical utility a

f these agents. The major factors include (1) blood clear-nce, (2) specific activity, (3) affinity of the tracer, (4) in vivotability, (5) nonspecific binding, and (6) blood flow anderfusion of tissue or organ of interest. The pathophysiolog-

cal mechanisms involved with some of the receptor bindingadiopharmaceuticals are discussed below:

epatobiliary System9mTc-labeled IDA derivatives (disofenin [Hepatolite®] andebrofenin [Choletec®]) are negatively charged lipophilic

omplexes, extracted by liver via the anionic receptors onepatocytes, and excreted into the bile duct, the gall bladder,nd ultimately into the intestine. In fasting individuals, theaxim microliter amount of liver uptake occurs approxi-ately by 10 minutes and peak gall bladder activity by 30 to

0 minutes after injection. The mechanism for the clearancef 99mTc-hepatobiliary agents involves hepatic extraction, he-atocyte binding, storage, and excretion into biliary canalic-li by an active transport process.9 Because bilirubin com-etes more avidly with the anionic receptor sites on theepatocytes, the liver uptake of 99mTc disofenin and mebro-enin is compromised at high bilirubin levels. In acute cho-ecystitis, prolonged fasting, acute pancreatitis, and severeiver disease can lead to nonvisualization of gall bladder.holecystokinin (CCK), synthetic CCK (Kinevac), and even

atty meal will cause the gall bladder to contract and thephincter of Oddi to relax, and increases the secretion of bile.

euroendocrine Tumorseuroendocrine tumors (NETs) are a heterogeneous groupf neoplasms originating from endocrine cells, which areharacterized by the presence of secretory granules as well ashe ability to produce biogenic amines and polypeptide hor-ones, such as somatostatin (SST). The diverse biological

ffects of SST are mediated through a family of G proteinoupled receptors of which 5 subtypes (SSTR1-5) have beendentified by molecular cloning.47 Because most NETs ex-ress SSTR-2 subtype, they can be successfully targeted withigh SA, 111In-DTPA-pentetreotide or OctreoScan®.69 Nor-

igure 12 131I-MIBG scan: Planar cardiac early (A) and delayed (B)mages in a normal subject. In contrast, the early (C) and delayedD) images in a patient with Parkinson’s disease show minimal or
bsent myocardial uptake of MIBG.

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al scintigraphic pattern includes visualization of organs,hich express SST receptors, including the thyroid, spleen,

iver, kidneys and, in some patients, the pituitary. Other or-ans are depicted at different times because of tracer excre-ion, including the renal collecting system and urinary blad-er, gallbladder, and bowel. Any uptake in nonphysiologicalreas reflects the presence of lesions with increased density ofST receptors, which can be related to malignant but some-imes also to benign lesions. Altered distribution of Oc-reoscan images (Fig. 11) show aberrant lung uptake in aatient with diffuse inflammatory processes, such as pulmo-ary interstitial fibrosis.

drenergic Presynapticeceptors and Storageumors arising from the neural crest share the characteristicf amine precursor uptake and decraboxylation and containarge amounts of adrenaline, dopamine and serotonin withinhe secretary granules in cytoplasm. Tumors of the adrenergicystem include pheochromocytoma (arise in adrenal medulla)r paragangliomas (extraadrenal tissue) and neuroblastomas.

Figure 13 Biodistribution of 111In-Zevalin®: (A) Normalwith 90Y-Zevalin®. (B) Abnormal biodistribution at 3 an
is not eligible for therapy.
31I or 123I labeled meta-iodobenzylguanidine (MIBG) is usedpecifically to depict and localize catecholamine-secreting tu-ors.42 MIBG structurally resembles norepinephrine and, to

ome extent, shares its biological behavior in that it is takenp by an active, sodium- and energy-dependent amine up-ake mechanism (uptake 1) in the cell membrane of sympa-homedullary tissues and is stored into the intracellular cat-cholamine storing granules by another specific, activeptake mechanism.69 The normal distribution usually showsptake in the salivary glands, spleen, liver, and urinary blad-er. Heart, lungs, colon, and kidneys were less frequentlyisualized. Thyroid and stomach uptake are primarily due toree radio iodide species due to in vivo dehalogenation.42

ilateral symmetric activity is sometimes evident in the necknd shoulders of children, and it seems to be related to up-ake in brown adipose tissue. MIBG imaging is characterizedy high specificity with very few (1%-5%) false-positive find-

ngs, ie, because of retention of radioactivity in the urinaryract, or the presence of adrenal hyperplasia following con-ralateral adrenalectomy or very rarely to non-NET or benignesions.69

ution at 4 and 86 hours and patient eligible for therapyours showing increased bone marrow uptake. Patients

distribd 24 h

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Because MIBG uptake is dependent on the expression ofET on the presynaptic adrenergic neurons of the heart,IBG imaging has a diagnostic role in the assessment of

atients with cardiomyopathy and heart failure.70 MIBG car-iac uptake was shown to be significantly decreased (Fig. 12)

n patients with dementia and movement disorders, such asarkinson’s disease.71,72

ntibody Imagingost cancer cells and synthesize many proteins or glycopro-

eins that are antigenic in nature. These antigens may bentracellular, or expressed on the cell surface or shed or se-reted from the cell into extracellular fluid or circulation.umor-associated antigens and receptors present on the tu-or cell surface include prostate-specific membrane antigen

PSMA) and CD20 antigen on lymphoma cells. The 3 impor-ant FDA approved radiolabeled monoclonal antibodiesmAbs) are ProstaScint® for diagnostic imaging and Zeva-in® and Bexxar® for radioimmunotherapy.73-76 Imagingtudies with 111In-Zevalin are essential to determine eligibil-ty for radioimmunotherapy with 90Y-Zevalin. In contrast,atients receiving 131I-Bexxar therapeutic regimen involvesbtaining 3 whole-body scans during the week after a smallose (185 MBq) of 131I-Bexxar administered only for pur-oses of determining the residence time, which is necessaryo determine the therapeutic dose. Imaging studies, however,re not performed to determine targeting or to assess biodis-

igure 14 99mTc-MDP bone scan demonstrating decreased thoracicpine uptake due to prior radiation therapy.

ribution. b

rostaScintSMA is more highly expressed in malignant prostate cellsompared with nonmalignant cells. A murine IgG1 mAbmAb 7E11-C5.3) Conjugated to the 111In chelator GYK-TPA to form the immunoconjugate, 111In capromab pen-etide (ProstaScint). There is a high degree of tumor bindingo all prostate cancers tested in vitro and a very high degree ofpecificity. ProstaScint uptake by tumor cells in vivo is de-endent on the degree of PSMA expression. PMSA may bexpressed by a small number of nonprostatic malignant tu-ors (renal cell carcinoma and small cell carcinoma of the

ung), and these can result in false-positive examinations.ProstaScint imaging has been advocated in patients with

ewly diagnosed prostate cancer, who are at risk for ad-anced disease, and for patients treated with definitive localherapy (prostatectomy or radiation therapy) who presentith increasing prostate-specific antigen levels.73 The inter-retation of ProstaScint SPECT images is challenging becausef the low spatial resolution of SPECT, and the nonspecificntibody localizations in normal blood pool. Some nonanti-en-dependent localization occurs, probably secondary toatabolism, in normal liver, spleen, and bone marrow. In

igure 15 Axial FDG-PET/CT images at the level of the aortic root inpatient with Takayasu’s arteritis. (A) A postpartum disease flairemonstrates transmural uptake at the aortic root and descendinghoracic aorta. Bilateral breast activity is seen secondary to breast-eeding. (B) After methotrexate therapy and cessation of lactation,
oth abnormalities recede.

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ertain subjects uptake in bowel, kidneys, and genitalia haseen observed. Human antimurine antibody caused by pre-ious exposure to murine-antibody products may alter thelearance and biodistribution of ProstaScint. Also, other med-cal problems or conditions, such as aneurysms, abdominal orowel adhesions, postoperative and colostomy or Inflammatory

esions may show unexpected uptake of radioactivity.

evalin®

he mAb moiety of Zevalin is ibritumomab, a murine IgG1

appa monoclonal antibody directed against the CD20 anti-en on lymphocytes (B cells). Radioimmunotherapy with0Y-Zevalin is indicated for the treatment of relapsed or re-ractory, low-grade follicular or B-cell non-Hodgkin’s lym-homa, including patients with rituximab-refractory follicu-

able 4 Pharmacologic and Toxic Effects of Drugs

Group of Drugs Dru

arcotic analgesics Morphine, codeine, oRoxicodone, Demer

anthine (theophilline and caffeine)containing medications

Aerolate, Slo-Phyllin,Excedrin, Midol, Caand soft drinks

eta blockers Acebutalol, atenolol,Tenerotec, Inderide

CE inhibitors Losartan, valsartan, A

IBG interactions Adrenergic neuron an

alcium channel blockers Verapamil, nifedipineLexxel

ytotoxic drugs Cyclophosphamide, vbleomycin,cis-platin

rugs altering hormonal status Stilboestrol, gonadotrcontraceptives

nhibitors of Na�/I� symporter(NIS)

Lugol’s iodine, iodideantithyroid drugs, c(Hypaque, Dionosil

rugs that can cause iatrogenicdisease

Paracetamol, aspirin,

Long-term use of conAminoglycoside antib

sulfonamides, fruseBleomycin, aminodaro

nitrofurantoinDoxorubicin

Adriamycin

rugs interfering with labelingcells

Hydralazine, methyldo

Digoxin

Antibiotics, corticosteroids

ar non-Hodgkin’s lymphoma.74,75 The therapeutic regimenonsists of an imaging study first with 111In-Zevalin (andituximab 250 mg m�2) on the day of injection, and again onays 2 to 3 to confirm appropriate biodistribution. Tumorptake may be visualized; however, tumor visualization onhe 111In-Zevalin scan is not required for 90Y-Zevalin therapy.he expected normal biodistribution includes (1) blood poolctivity in heart, abdomen, neck, and extremities, (2) mod-rately high to high uptake in normal liver and spleen, and3) moderately low or very low uptake in normal kidneys,rinary bladder, and normal (uninvolved) bowel. The criteriaor altered biodistribution (Fig. 13) are (1) an intense uptakef the radiotracer in RES (liver and spleen and bone marrow),2) diffuse uptake in normal lung more intense than the liver,

Pharmacologic and Toxic Effect

one, Percodan,thadone

Opioids constrict the Sphinctor of Oddi,which may cause nonvisualization ofthe intestine in hepatobiliary imaging

air, Anacin,coffee, Tea,

Block the vasodilatory effects ofadenosine

ol, propranolol, Prevent patients from reaching theirtarget heart rate during treadmillstress test

n Reduce GFR by blocking angiotensin IIreceptors or directly inhibiting theaction of renin

blockers Prevent MIBG uptake by inhibition ofreuptake of norepinephrine or depletestorage vesicle contents

zem, Lotrel, Interfere with stress testing and MIBGimaging studies

ine,osoureas

Decrease membrane transport andintracellular retention of major ogans(liver, kidney)

s, oral Increase the production of estrogen.induce gynecomastia andhyperprolactinemia

chlorate,t mediarast)

Competitive inhibition of NIS by anionsand prevent trapping of iodide bythyroid

ycline Cause liver toxicity and cause necrosisof liver cells

tive pill Cause the formation of hepatic tumorspenicillins,cyclosporin

Cause renal failure and decreaseglomerular filtration rate

usulphan, Causes lung disease and pulmonaryinterstitial fibrosis

Cardiotoxic and impairs left ventricularfunction

Cariotoxic and induces changes in cellmembrane permeability

Oxidation of stannous ion in the ktprevents labeling RBCs with Tc99m

Inhibits Na�/K�-ATPase pump andaffects membrane transport of RBCs

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able 5 Altered Biodistribution of Radiopharmaceuticals Attributable to Drug Interactions

Radiopharmaceutical Drugs Effects on the Imaging Study9mTc-MDP and 99mTc-HDP Aluminum containing drugs Reduced uptake in bone, increased

hepatic and renal uptakeIron salts High blood pool and renal activity diffuse

liver uptakeAmphotericin, cyclophosphamide, gentamicin,

vincristine, doxorubicinIncreased renal retention due to

nephrotoxicityDrugs causing gynecomastia, eg, stilboestrol,

spironolactone, phenothiazines, cimetidine, oralcontraceptives

Increased uptake in breast

Methotrexate Diffuse uptake in liver due tonephrotoxicity

Nifedipine Reduced bone uptakeDiphosphonates (etidronate, pamidronate) vitamin

D supplementsReduce bone uptake

9mTc-DISIDA (Hepatolite®)9mTc-Bida (Choletec®)

Narcotic analgesics (morphine, methadone) Delay in hepatic clearanceBarbiturates, cholecystokinin and analogs Enhanced biliary excretionNicotinic acid (chronic high doses) Abnormal or absence of tracer in

gallbladderTotal parental nutrition Reduced uptake into gallbladderErythromycin Increased liver uptake due to

hepatotoxicity9mTc-sulfur colloid Aluminum compounds, magnesium salts Flocculation of colloids, deposition in

lungAnesthetic agents (halothane) Shift of activity from liver to spleenEstrogens and androgens Abnormal uptake due to drug toxicityMethotrexate, cytosine arabinoside and

nitrosoureasIrregular liver uptake, shift of activity to

bone marrow and spleen9mTc-DTPA Al containing drugs Abnormal GFR

Nephrotoxic drugs (sulfonamides, cyclosporine) Reduced GFRAngiotensin-converting enzyme inhibitors, diuretics,

such as furosemideReduced GFR

Dipyridamole infusion Reduced GFR9mTc-DMSA Ammonium chloride, sodium bicarbonate Reduced renal uptake, increased liver

uptakeAngiotensin-converting enzyme inhibitors Reduced renal uptake in renal artery

stenosis9mTc-RBC (in vivo labeling) Heparin, dextran, penicillin, hydralazine,

doxorubicin, iodinated contrast mediaPoor labeling, increased uptake in

thyroid, and stomach23I/131I sodium iodide9mTc pertechnetate

Iodine-containing compounds (SSKI, Lugol’ssolution)

Reduced uptake in thyroid

Antithyroid drugs (propylthiouracil, Topazol) Reduced uptake in thyroidThyroid supplements (Cytomel, Synthroid) Reduced uptake in thyroidMeprobamate, phenylbutazone, sulfonamides,

corticosteroids, ACTH, sulfonylureas, perchlorate,antihistamines

Reduced uptake in thyroid

31I-mIBG Antihypertensives (Lebatolol, reserpine, adrenergicneuron blockers)

Inhibition of tumor and myocardialuptake

Sympathomimetics (phenylpropanolamine,imipramine)

Decrease in cardiac uptake

Nifedipine Increased tumor uptake and delay inwashout

Antidepressants (tricyclics, maprotiline, trazodone) Reduced tumor uptakeAntipsychotics (phenothiazens, thioxanthines) Educed tumor uptake

7Ga citrate Cytotoxic drugs (cisplatin, methotrexate,cyclophosphamide, vincristine)

Reduced tumor/abscess and hepaticuptake increased blood pool, skeletaland renal activity

Bleomycin, busulphan, amiodarone, nitrofurantoin,methotrexate, cyclophosmamide

Abnormal uptake in lung (drug-inducedpulmonary interstitial pneumonitis and/
or fibrosis)

ar

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nd (3) kidney uptake is greater than the liver on the poste-ior view.76

actors Causedy Medical Procedures

he biodistribution of radiopharmaceuticals may also be al-ered significantly because of medical procedures, such asadiation therapy surgery, and hemodialysis.2,77 The effects ofadiotherapy on the biodistribution of several radiopharma-euticals have been well documented, and depending uponhe radiation dose level, the effects may be transient or per-anent in nature.77 In the early phase of radiation therapy, an

nflammatory response may be predominant with increasedascular permeability and leukocyte migration. In bonecans, 99mTc-MDP activity in soft-tissue areas within a radia-ion field may increase.78 The long-term effect of radiationherapy is reduced blood flow as the result of fibrosis, and asresult, the bone uptake of 99mTc-MDP may be significantly

educed (Fig. 14). The local effects of radiation-causing os-eoblastic suppression and hepatitis with defective uptake,espectively, of bone-seeking radiotracers and colloids areidely recognized. Also, following radiation therapy, iron-verload may lead to decrease in iron-binding capacity ofron.32 As a result, the biodistribution of 67Ga-citrate is sig-ificantly altered showing increased bone uptake and de-reased soft tissue uptake in the irradiated areas.77 Flare phe-omenon in FDG-PET (Fig. 15) showing an increase in

able 5 Continued

Radiopharmaceutical Drugs

CorticosteroidsDrugs causing hyperprolactine

stilboestrol, methyldopa, mecimetidine, gonadotropins)

Frusemide, phenylbutazone, ibsulfonamides, penicillins, ce

11In-pentetreotide(Ocreoscan®)

Somatostatin analogues (octre

11In and 99mTc-leukocytes(WBCs)

Antibiotics and steroids

01Tl-thallous chloride �-blockers and nitrate

VasopressinDoxorubicin

Inhibitors of Na–K ATPase pumfurosemide)

18F]FDG Insulin in patients with hyperg

Benzodiazepines

Growth factors (hepatocyte grgranulocyte/macrophage colfactor) and erythropoietin

tandard uptake values in the tumor or soft-tissue disease, d

as been reported during post therapy (chemotherapy and/oradiation therapy) follow-up period.56,79,80 The increasedDG uptake may confound estimation of treatment responser may also indicate recurrent disease.Recent surgery commonly results in the accumulation of

adiopharmaceuticals in scars and tissues around the opera-ion site probably due to local edema. 67Ga citrate and 99mTc-

DP show increased localization in operative sites and tissuedjacent to prostheses. Also, FDG and radiolabeled cells maylso show uptake at surgical sites. Defibrillation has beenound to result in increased uptake of 99mTc-MDP in the chestall tissues.Chronic renal failure and dialysis (both hemo- and perito-

eal dialysis) are fairly well known causes of altered clearancend biodistribution of several radiopharmaceuticals. Elimi-ation of most radiopharmaceuticals is disrupted in patientsith compromised renal function, resulting in prolongedlood pool activity, and possibly increased clearance throughhe liver. In hemodialysis, small solute molecules, such as9mTc-chelating agents and radioiodide, move from the areaf high concentration in blood to the area of lower concen-ration in the dialyzate. Renal dialysis substitutes for kidneylimination. Often, dialysis will not adversely affect the im-ging results as long as the administered radiopharmaceuticalas been given time to localize in its organ of interest beforeeginning dialysis. However, the components of the dialyzateuid that enter the patient’s bloodstream may cause veryoticeable alterations in how a radiopharmaceutical is han-

Effects on the Imaging Study

Absence or reduced tumor sizehenothiazines,ramide,

Increased uptake in breast

n,porins

Delayed and increased renal uptake dueto drug-induced interstitial nephritis

or Sandostatin) Reduced tumor, splenic, hepatic andrenal uptake enhanced detection ofhepatic metastases

May cause reduced uptake of leukocytes

Decreased Number and size of exercise-induced perfusion defects

Perfusion defects in the absence of CADReduced myocardial uptake caused by

cardiotoxicityabain, Decrease the uptake of tumor and

myocardial cellsia Increased uptake in tumor and skeletal

muscleDecrease paraspinal and posterior

cervical muscle uptake in tensepatients

actor,imulating

Increased diffuse intense uptake in bonemarrow, and spleen

mia (ptoclop

uprofephalosotide

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owth fony st

led by the patient’s body. In contrast, peritoneal dialysis

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emoves metabolic waste from blood by use of the patient’swn semipermiable membrane—the peritoneal membrane.ialyzate is placed into the patient’s peritoneal cavity where itccumulates radioactivity that passes through the peritonealembrane along concentration and osmotic pressure gradi-

nts.

actors Causey Pharmacologicactors and Drug Interactions

here is considerable evidence that the biodistribution orharmacokinetics of radiopharmaceuticals may be altered byatient medication.2,5-7,77 Many reports on drug/radiophar-aceutical interactions are anecdotal, and in some instancesdirect cause and effect relationship has not been unequiv-cally established. The drug and radiopharmaceutical inter-ctions may arise because of the pharmacologic action of therug or due to physicochemical interactions between therug and radiophamaceutical. Even contamination with an-iseptics during dispensing or administration can also lead tolterations in the biodistribution of the tracer. Many drugs inveryday use may cause or aggravate disease, and that theatrogenic (drug induced) disease itself may then produce annexpected biodistribution of the radiopharmaceutical.rug/radiopharmaceutical effects may be classified by organf interest, radiopharmaceutical used, chemical class of therug, or the type of drug interaction.Drugs that alter the functional status of an organ will have

ignificant effect on the biodistribution of radiopharmaceu-icals. Some of the important groups of drugs and their phar-acologic effect are summarized in Table 4. Drug interac-

ions with radiopharmaceuticals and the correspondingffects on imaging studies are summarized in Table 5. Drugnterference with mIBG uptake in a patient with metastaticaraganglioma is shown in Fig. 16. During earlier therapies,

31I-mIBG uptake in the metastatic lesions was very high. Aosttherapeutic whole-body scan after recent mIBG therapy

Figure 16 Drug interference with MIBG uptake in a patientherapeutic dose shows uptake in the metastatic lesionmajority of metastatic lesions identified by FDG-PET. Thto recreational drugs (such as cocaine, ephedrine) taken

ailed to detect the vast majority of metastatic lesions. FDG- 1

ET, however, showed metastases with a similar distributiono the initial mIBG scan. The most likely cause of this “falsecan” is the rapid interference of recreational drugs (such asocaine, ephedrine) with the mIBG uptake, which probablyere taken just before the recent mIBG therapy.81

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1

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