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