Nuclear Medicine
Michael R. Lewis, Ph.D.Associate Professor
Department of Veterinary Medicine & Surgery
Department of Radiology
Nuclear Science & Engineering Institute
Fisson/Reactor Products Cyclotron Products
• Generally decay by - emission because of excess neutrons
• Not many are useful for diagnostic imaging, but several are useful for radiotherapy
• Generally decay by + emission or electron capture because of excess protons
• Many are useful for diagnostic imaging
(gamma scintigraphy or positron emission tomography)
Definition of Radiopharmaceutical
• Radioactive compound used for diagnosis and/or therapy of diseases
• In nuclear medicine, ~95% of radiopharmaceuticals used for diagnosis, while the rest are used for therapy
• Radiopharmaceuticals have no pharmacologic effect, since they are used in tracer quantities
Ideal Radiopharmaceutical for Imaging -Factors to Consider
• Administering to patients– What is the radiation dose to normal organs?– Radiochemical and radionuclidic purity must
be extremely high– Regulatory approval required for human use
• Scope and limitations of instrumentation– Gamma scintigraphy vs. single photon
emission computed tomography (SPECT) vs. positron emission tomography (PET)
Ideal Physical Characteristics of Imaging Radiopharmaceutical
• Decay Mode– gamma (gamma scintigraphy) or positron (PET) and - emitters avoided if at all possible; cause
higher absorbed dose to organs and tissues
• “Good” Energy emissions of radionuclide– Easily collimated and shielded (lower dose to
personnel)– easily detected using NaI crystals (e.g. Tc-99m
decays by 140 keV photons which is ideal)– low radiation dose to the patient (no or )
Ideal Physical Characteristics of Imaging Radiopharmaceutical
• Ideal half-life– long enough to formulate RaPh and accomplish
imaging study– short enough to reduce overall radiation dose to
the patient– physical half-life of radionuclide should be
matched well to biological half-life of RaPh
• Readily Available– geographic distance between user and supplier
limits availability of short-lived radionuclides/RaPh– Generator-produced radionuclides are desirable
Ideal Biological Characteristics of Radiopharmaceutical
• Ideal biological half-life– long enough to complete the procedure
(i.e. localize to target tissue while minimizing background)
– short enough to reduce overall radiation dose to the patient
• High target:non-target ratio– rapid blood clearance– rapid localization in target tissue– rapid clearance from non-target tissues (liver,
kidney, intestines)
Radioactive Decay Processes
1. alpha ++
2. beta minus -
3. beta plus + 4. e- capture EC 5. isomeric transition 6. Internal conversion IC
Diagnostic Nuclear Medicine
Anatomic vs. Physiologic Imaging
How does Physiologic Imaging Work?
Anatomy vs. Function in a broken leg
Anatomy vs. Physiology
Gamma Camera
• device most commonly used to obtain an image in nuclear medicine
• sometimes called a scintillation camera or Anger camera
• camera obtains an image of the distribution of a RaPh in the body (or organ) by detection of emitted -rays
Gamma Camera Consists of…
• A collimator• sodium iodide crystal (detector)• photomultiplier (PM) tube array• position circuit• summation circuit• pulse height analyzer
Sodium Iodide Detector
• Gamma rays which interact in the crystal will deposit energy in the crystal to produce “fast electrons” with high kinetic energy
• Mechanisms of interaction are:– Photoelectric effect– Compton scatter– Pair production (not relevant to NM)
Sodium Iodide Detector, cont’d...
• As electrons slow down in crystal their KE is converted, in part, into light scintillations
• A relatively constant proportion of the light scintillations (produced by each -ray) will exit the crystal and hit the photocathode of the photomultiplier tube
• The crystals used in gamma cameras are typically 40-60 cm in diameter and 1 cm thick
Collimator
• The purpose of the collimator is to define a field of view
• each very small area of the detector ‘sees’ only a small part of the organ to be imaged
• two basic types of collimators:– multi-hole (4000-10000 holes) (used more in
modern gamma cameras)– single or pin-hole
Gamma Camera Basics*
*JPNM Physics website
GE Whole Body Gamma Camera
SPECT Imaging
Mo-99/Tc-99m GeneratorColumn Chromatography
When saline is passedover column, the 99mTcO4
-
is dissolved and lessstrongly adsorbed to alumina.
Cardiac Infarction
201TlCl Rest99mTc-Sestamibi
Stress Test
Cardiac Ischemia
201TlCl Rest99mTc-Sestamibi
Stress Test
O
PHO O
OH
P
O
OH
OH
O
PHOH2C
OH
P
O
OH
OH
C
CH3
Pyrophosphate
OH
C
Methylenediphosphonate
H
OH
Hydroxyethylenediphosphonate
Hydroxymethylenediphosphonate
Inorganic Phosphate Organic Phosphates
(MDP)
(EDP)
(HDP)
Normal Canine Bone Scan
• 99mTc-MDP (Methylene Diphosphonate)
Rib Metastasis
11-year old boy with a one month history of right kneepain
Increase activity in the righttibia
Diagnosis: Osteosarcoma
Juvenile Osteosarcoma
Metastatic Prostate Carcinoma
Imaging
99mTc-HDP
Principle of PET Imaging
Each annihilation produces two 511 keV photons traveling in opposite directions (180O) which are detected by the detectors surrounding the subject
GLUT
PLASMA TISSUE
FDG
Fluorodeoxyglucose MetabolismFluorodeoxyglucose Metabolism
12
O
18F
HOHO
OH
OH12
O
18F
HOHO
OH
OH
12
O
18F
HOHO
OH
HKO P
[18F]Fluorodeoxyglucose (FDG)
PET
Control Alzheimer’s Disease
Center for Functional Imaging; Life Sciences Division; Lawrence Berkeley National Laboratory; Berkeley, CA.
Brain Metabolism ([18F]FDG)
[11C]Raclopride PET Brain Study
Normal
Cocaine Abuser
Courtesy BNL PET Project
nCi/cc1000
800
600
400
200
0
Therapeutic Nuclear Medicine
Fission products useful in nuclear medicine include:99Mo, 131I, 133Xe, 137Cs and 90Sr
Mo-99 I-131
DifferentiatedThyroid
Carcinoma
5 mCi Na131I
ImagingTreatment Planning
48 h p.i.
DifferentiatedThyroid
Carcinoma
Therapy
105 mCi Na131I
27 h p.i.
Differentiated Thyroid CarcinomaPost Surgical Resection
Therapy57Co Flood Source + 105 mCi Na131I
Differentiated Thyroid Carcinoma
201TlCl and 99mTc-Sestamibi Imaging
4 months after Na131I Therapy
Canine OsteosarcomaTumor distal radius
Story of QuadraMetTM -- I
• 153Sm identified as a useful nuclide for radiotherapy by MU researchers
• Development began in early 1980’s at MU in collaboration with the Dow Chemical Company [phosphonate ligand complexes;153Sm-EDTMP]
• Successful in treatment of primary osteosarcoma in canine patients, with added bonus of 18% cure rate [MU College of Veterinary Medicine]
One of Our First Patients
Bone Scans of Canine Patient
Before Treatment: 8/15/85 After Treatment: 3/3/86
Results of Clinical Trial of153Sm-EDTMP in Canine Osteosarcoma
Response # of Dogs (%) Survival (months)
Disease Free 7 (18%) 11 - 60
Partial Response 25 (62%) 1 - 16
No Response 8 (20%) 0.5 - 1
Story of QuadraMet™ -- II
• Clinical trials began in late 1980’s, with doses supplied by MURR for Phase I studies
• ~80% efficacy, with ~25% obtaining full pain remission
• Approved in U.S. for pain palliation of metastatic bone cancer in March, 1997
153Sm-EDTMP [QuadraMet]99m99mTc-MDPTc-MDP 153153Sm-EDTMPSm-EDTMP
NN
PO3H2
PO3H2
PO3H2
PO3H2
153153SmSm
+
Experimental Nuclear Medicine
1. Targeting vector (e.g., mAb, peptide hormone, small molecule, etc.)
2. Radionuclide (e.g., diagnostic – 99mTc, 111In, etc.; therapeutic – 188Re, 90Y, 177Lu, etc.)
3. Bifunctional chelating agent (BCA)4. Linker or spacer
The design of an effective tumor-targeting radio-pharmaceutical involves appropriate selection of:
Radiopharmaceutical Design
TargetingVector
LinkerBifunctional
Chelating Agent
MRadiometal
Hypothesis 1
Non-invasive imaging of bcl-2 mRNA expression in lymphoma may aid in the identification of chemotherapy patient risk groups, who might respond better to targeted immunotherapy, radioimmunotherapy, or antisense therapy.
Receptor Targeting for Molecular Imaging and Therapy
• Radiometal chelation should be stable under physiological conditions.
• Chelate modification should not lower the receptor binding affinity.
Internalizing vs. Non-internalizingReceptors
Bryan JN, et al. Vet. Comp. Oncol. 2004; 2:82-90 Courtesy of Derek B. Fox, D.V.M., Ph.D.
Peptide Nucleic Acid
O
O
B
O P O
O
O-
O
B
O P O
O
O-
O
B
O
N
O
HN
NH
O
B
N
O
NH
O
B
N
O
HN
O
B
DNA
PNA
Cellular Delivery of PNA
Chelator PNA Peptide
DOTA-Tyr3-Octreotate
*M = 111In for gamma scintigraphy and single photon emission tomography (SPECT), 64Cu for positron emission tomography (PET), or 177Lu for targeted radiotherapy (TRT).
N
ONH
D Phe Cys Tyr D Trp
LysThrCysThr
N
N N
COOH COOH
COOH
SS
*M HOOC
PNA and Peptide Conjugates
NN
N NCOOH
HOOC
HOOC
O
NH CCAGCGTGCGCCAT-dPhe-Cys-Tyr-dTrp-Lys-Thr-Cys-Thr(OH)
S S
R1
R2
DOTA-anti-bcl-2-PNA-Tyr3-octreotate
DOTA-Nonsense PNA-Tyr3-octreotateR1= TTGCGACCCTCTTG-dPhe
R2= Cys-Ala-Ala-Ala-Ala-Cys-Thr(OH) DOTA-anti-bcl-2-PNA-Ala
S S
R1= dPhe DOTA-Tyr3-octreotate
MicroSPECT/CT Using 111In-labeledPNA and Peptide Conjugates
(1 h, 48 h)
Antisense
Nonsense
Ala
TATE
Jia F, et al. J. Nucl. Med. 2008; 49: 430-438
Bcl-2 mRNA Expression Levelsin Mec-1 and Ramos Cells
Mec-1 Ramos0
5
102000
2500
3000
3500
4000
Bcl
-2 m
RN
A c
opy
num
ber
rati
o3821
1
(Bcl-2 +) (Bcl-2 -)
MicroSPECT/CT Using111In-DOTA-anti-bcl-2-PNA-Tyr3-octreotate
(48 h)
Mec-1 Ramos
MicroPET/CT Using64Cu-DOTA-anti-bcl-2-PNA-Tyr3-octreotate
Mec-1
Ramos
1 h 3 h 24 h 48 h
Hypothesis 2
Dogs with naturally occurring B-cell
lymphoma will demonstrate tumor
specific uptake of 111In-anti-bcl-2-PNA-
Tyr3-octreotate that correlates
negatively with response to
chemotherapy.
111In-DOTA-Tyr3-OctreotateScintigraphy
Nodes
1 h post-injection 4 h post-injection 24 h post-injection
PNA Imaging of Normal Dog
Partial Remission
Initial Scan
Remission Scan
Complete Remission
Initial Scan
Remission Scan
Relapse Scan
Hypothesis 3
Combined radionuclide and antisense therapy may act synergistically or additively with respect to cell proliferation and viability in an in vitro model of B-cell lymphoma.
Western Blot Analysis
Tubulin
bcl-2
1 2 3 4 5
1. Cells without treatment2. Cells treated with 2 μg of DOTA-anti-bcl-2-PNA-Tyr3-octreotate for 48 h3. Cells without treatment4. Cells treated with 2 μg of DOTA-nonsense-PNA-Tyr3-octreotate for 48h 5. Cells treated with 2 μg of DOTA-anti-bcl-2-PNA-Ala for 48 h
Cell Viability Assay
Day 2 p<0.002
Day 3 p<0.005
177-Lu Labeled PNA Peptide Conjugate
0 1 2 3
60
70
80
90
100
2 g Cold PNA Control2 Gy/ 2g2 Gy/ 5g2 Gy/ 10g
Day
TUNEL Assays
Anti-bcl-2 + Anti-FLIP Anti-bcl-2 + CH11 Anti-bcl-2 Anti-FLIP + CH11
Anti-bcl-2 + Anti-FLIP Anti-bcl-2 + CH11 Anti-bcl-2 Anti-FLIP + CH11SH-SY5Y
IMR-32
AcknowledgmentsAcknowledgments
Dr. Carolyn Anderson Washington University
Dr. Henry VanBrocklin Lawrence Berkeley Lab
Dr. Joanna Fowler Brookhaven National Lab
Dr. Gregory Daniel University of Tennessee
Dr. Alan Ketring University of Missouri
Dr. Wynn Volkert University of Missouri