Transcript Radiation Biology 328 2008 Slides - University of Missouri

Nuclear Medicine
Michael R. Lewis, Ph.D.
Associate Professor
Department of Veterinary Medicine & Surgery
Department of Radiology
Nuclear Science & Engineering Institute
Fisson/Reactor Products
• Generally decay by bemission because of
excess neutrons
• Not many are useful
for diagnostic
imaging, but several
are useful for
radiotherapy
Cyclotron Products
• Generally decay by b+
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)
 a and b- 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 a or b)
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.
2.
3.
4.
5.
6.
alpha
beta minus
beta plus
e- capture
isomeric transition
Internal conversion
a++
bb+
EC

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 Generator
Column Chromatography
When saline is passed
over column, the 99mTcO4is dissolved and less
strongly adsorbed to
alumina.
Cardiac
Infarction
201TlCl
Rest
99mTc-Sestamibi
Stress Test
Cardiac
Ischemia
201TlCl
Rest
99mTc-Sestamibi
Stress Test
Inorganic Phosphate
O
HO
P
OH
Organic Phosphates
O
O
P
O
OH
HO
OH
Pyrophosphate
P
OH
O
H2
C
P
OH
OH
Methylenediphosphonate
(MDP)
OH
C
Hydroxyethylene
diphosphonate
(EDP)
CH3
OH
C
H
Hydroxymethylene
diphosphonate
(HDP)
Normal Canine Bone Scan
•
99mTc-MDP
(Methylene Diphosphonate)
Rib Metastasis
Juvenile Osteosarcoma
11-year old boy with a one
month history of right knee
pain
Increase activity in the right
tibia
Diagnosis: 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
Fluorodeoxyglucose Metabolism
PLASMA
G
L
U
T
OH
HO
HO
O
2
1
18
F
FDG
OH
TISSUE
O P
OH
HO
HO
O
2
HK
1
18
F
OH
HO
HO
O
2
1
18
F
OH
[18F]Fluorodeoxyglucose (FDG)
PET
Brain Metabolism ([18F]FDG)
Control
Alzheimer’s Disease
Center for Functional Imaging; Life Sciences
Division; Lawrence Berkeley National
Laboratory; Berkeley, CA.
[11C]Raclopride PET Brain Study
Normal
nCi/cc
1000
800
600
Cocaine Abuser
400
200
0
Courtesy BNL PET Project
Therapeutic Nuclear Medicine
Mo-99
I-131
Fission products useful in nuclear medicine include:
99Mo, 131I, 133Xe, 137Cs and 90Sr
Differentiated
Thyroid
Carcinoma
5 mCi Na131I
Imaging
Treatment Planning
48 h p.i.
Differentiated
Thyroid
Carcinoma
Therapy
105 mCi Na131I
27 h p.i.
Differentiated Thyroid Carcinoma
Post Surgical Resection
Therapy
57Co Flood Source + 105 mCi Na131I
Differentiated Thyroid Carcinoma
201TlCl
and 99mTc-Sestamibi Imaging
4 months after Na131I Therapy
Canine Osteosarcoma
Tumor 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 of
153Sm-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]
99mTc-MDP
PO3H2
PO3H2
N
N
PO3H2
PO3H2
+
153Sm
153Sm-EDTMP
Experimental Nuclear Medicine
Radiopharmaceutical Design
The design of an effective tumor-targeting radiopharmaceutical involves appropriate selection of:
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
M
Radiometal
Linker
Bifunctional
Chelating Agent
Targeting
Vector
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-internalizing
Receptors
Bryan JN, et al. Vet. Comp. Oncol. 2004; 2:82-90 Courtesy of Derek B. Fox, D.V.M., Ph.D.
Peptide Nucleic Acid
PNA
B
B
B
O
N
H
N
N
NH
O
O
O
B
B
B
O
O
O
O
H
N
N
NH
O
DNA
O
O
P
O-
O
O
O
O
P
O-
O
O
Cellular Delivery of PNA
Chelator
PNA
Peptide
DOTA-Tyr3-Octreotate
O
COOH
N
N
H
D Phe
N
*M
N
COOH
HOOC
Cys
S
S
Thr Cys
Tyr
Thr
D Trp
Lys
N
COOH
*M = 111In for gamma scintigraphy and single
photon emission tomography (SPECT), 64Cu for
positron emission tomography (PET), or 177Lu for
targeted radiotherapy (TRT).
PNA and Peptide Conjugates
NH
HOOC
HOOC
N
N
N
N
O
CCAGCGTGCGCCAT-dPhe-Cys-Tyr-dTrp-Lys-Thr-Cys-Thr(OH)
R1
S
S
COOH
R2
DOTA-anti-bcl-2-PNA-Tyr3-octreotate
DOTA-Tyr3-octreotate
R1= dPhe
R1= TTGCGACCCTCTTG-dPhe
DOTA-Nonsense PNA-Tyr3-octreotate
R2= Cys-Ala-Ala-Ala-Ala-Cys-Thr(OH) DOTA-anti-bcl-2-PNA-Ala
S
S
MicroSPECT/CT Using 111In-labeled
PNA and Peptide Conjugates
(1 h, 48 h)
TATE
Antisense
Jia F, et al. J. Nucl. Med. 2008; 49: 430-438
Nonsense
Ala
Bcl-2 mRNA Expression Levels
in Mec-1 and Ramos Cells
Bcl-2 mRNA copy
number ratio
4000
3821
3500
3000
2500
2000
10
5
1
0
Mec-1
(Bcl-2 +)
Ramos
(Bcl-2 -)
MicroSPECT/CT Using
111In-DOTA-anti-bcl-2-PNA-Tyr3-octreotate
(48 h)
Mec-1
Ramos
MicroPET/CT Using
64Cu-DOTA-anti-bcl-2-PNA-Tyr3-octreotate
Mec-1
1h
Ramos
3h
24 h
48 h
Hypothesis 2
Dogs with naturally occurring B-cell
lymphoma will demonstrate tumor
specific uptake of 111In-anti-bcl-2-PNATyr3-octreotate that correlates
negatively with response to
chemotherapy.
111In-DOTA-Tyr3-Octreotate
Scintigraphy
1 h post-injection
4 h post-injection
Nodes
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 treatment
2. Cells treated with 2 μg of DOTA-anti-bcl-2-PNA-Tyr3-octreotate
for 48 h
3. Cells without treatment
4. 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
TUNEL Assays
Anti-bcl-2 + Anti-FLIP
Anti-bcl-2 + Anti-FLIP
IMR-32
Anti-bcl-2 + CH11
SH-SY5Y
Anti-bcl-2 + CH11
Anti-bcl-2 Anti-FLIP + CH11
Anti-bcl-2 Anti-FLIP + CH11
Acknowledgments
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