METALS IN MEDICINE

APPLICATIONS OF

METALS IN MEDICINE

AT ANSTO

RADIOPHARMACEUTICAL R & D

Andrew Katsifis

19 January 2004

THE RADIOTRACER

Claude BERNARD

Henri BECQUEREL

George HEVESY

Claude Bernard me disait un jour «Nous sauronsla Physiologie lorsque nous pourrons suivre pas à pas une molécule de carbone ou d’azote, faire sonhistoire, raconter son voyage dans le corps (d’unchien), depuis son entrée jusqu’à sa sortie»

Taine, H.H., Histoire de la France,1891, 7,28

the concept

the toolthe idea

Molecular Imaging in Nuclear Medicine

Injection

Precursor

Radionuclide

Human

QC/QA

Radiopharmaceutical

PET SPECTRADIOLABELLING RADIOPHARMACOLOGY

0.0

0.5

1.0

1.5

2.0

CEREBELLUM COLLICULI DIENCEPHALON STRIATUM FRONT CTX

%ID/g

CONTROL

GBR 12909

Citalopram

Purification

METALS IN MEDICINE

Multidisciplinary group: Chemists, Biologists, Pharmacologists, Physicists.

Synthetic Chemistry- Ligand, Conjugates Drug Synthesis-Receptor Molecules Separation and Analytical technologies In vitro and In vivo evaluation (Animal Models) Autoradiography, Metabolite Analysis Radionuclide Source- Cyclotron and Reactor SPECT-CT Animal Imaging(CT-SPECT, PET) Clinical Trials Extensive national and international links

Radiopharmaceuticals R&D

Gamma Camera

Compact system designed for animal studies

Dual-head gamma cameras with CT

Pinhole Collimators

METALS IN MEDICINE

METALS IN MEDICINE

OBJECTIVES

Radiopharmaceuticals R&D are Developing Target-Specific

Radiolabeled Pharmaceuticals for Diagnosis and Therapy of Disease

PURPOSE

METALS IN MEDICINE

Isotope t 1/2

(h)Emission Function

99mTc 6.5 Oncology, Cardiology,Neurology

201Tl 73.1 Cardiology, Oncology67Ga 78.2 Oncology, Infection,

Inflammation111In 67.4 Oncology, Infection,

Inflammation

51Cr, 94mTc, 68Ga, 62/64/67Cu, 86Y, 57/58Co

METALS IN MEDICINE

Isotope t 1/2

(d)Emission Function

117mSn 13.6 Oncology-Bone-Palliative153Sm 1.95 Oncology-Bone-Palliative77Lu 6.7 Oncology188Re 0.7 Oncology, Restenosis

90Y 2.7 Oncology, Restenosis212Bi 1 h Oncology

225Ac, 199Au, 105Rh, 109Pd, 111Ag, 143Pr, 186Re, 64Cu

METALS IN MEDICINE

RATIONALE FOR RADIOPHARMACEUTICAL DESIGN

Few Metals Target Specific Tissues/Organs

201Tl mimics K, 67Ga-Fe and 89Sr-Ca

For biological activity most other “metallic”

radioisotopes must be chelated to form complexes

or linked to specific targeting entities

METALS IN MEDICINE

Selection of radioisotope for biological use is primarily determined by the isotope’s decay characteristics

Radiopharmaceutical design is based on the intended use, targeting molecules and the physico-chemical properties of isotope.

Nature of the complex will determine biological activity

RATIONALE FOR RADIOPHARMACEUTICAL DESIGN

METALS IN MEDICINE

Emission (, +, -,

Radionuclide purity

Specific activity

Half-life

Chemical/physical properties

Ease of production/cost

“METAL” ISOTOPE REQUIREMENTS

METALS IN MEDICINE

H3C

H3C NH

N

HN CH3

CH3

H3C CH3

OH OH

N

HMPAO

CH3 O C

CH3

CH3

N

MIBI

P P

O

HO

OH OH

O

OH

MDP

OH

Tc

OH

O O

OO

P

P

O OH

OOH

P

P

OHO

OHO

99mTcMDP

METALS IN MEDICINE

NH HN

NN

OH OH

H3C CH3

H3C CH3

H3C CH3 N N

NN

O O

H3C CH3

H3C CH3

H3C CH3

Tc

OSn2+

H

+ 99mTcO4-

Tc-99m HMPAOTc-99m HMPAO(Ceretec)(Ceretec)

METALS IN MEDICINE

99m99mTc HMPAOTc HMPAO (Ceretec)(Ceretec)

METALS IN MEDICINE

Ictal HMPAO SPECT

Inter - Ictal HMPAO SPECT

PET

99mTc-MIBI

METALS IN MEDICINE

+1

O

O

OO

C

N

C

N

Tc

CN

CN

CN

CN

O

O

METALS IN MEDICINE

99mTc-Trodat-Brain Receptor Imaging

METALS IN MEDICINE

NCH3

Cl

TcN

S

N

SO

99mTc-TRODAT

NCOOCH3

CH3

F

CFT

99mTc-TRODAT-1 SPECT intransverse views of healthy volunteer (A)and of patients with stage I (B) and stage II (C) Parkinson’s disease. Asymmetric striatal uptake was observed, with more profound loss contralateral to symptoms or more affected limbs.

METALS IN MEDICINE

METALS IN MEDICINE

Known Receptor Ligand

Isotope

Conjugate Design

Isotope

Receptor Ligand

Integrated Design

METALS IN MEDICINE

O NH

SH

HN

HN

O

COOH

O

MAG-3

R

N

N

N

N

R

R

COOH

TETRA-AMINE HYNIC

N

COOH

N

NH

AMINO-Tc(CO)3

Tc

CO

CO

N

R

CO

N

NH

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Receptor target identical

Receptor affinity identical

Pharmacokinetics different

Unit target uptake different

Biodistribution different

Clearance rate different

Clearance route different

Metabolism different

Stability is different

PEPTIDE

MAG-3

HN

O NH

SH

HN

HN

O

C

O

O

HYNIC

O

HN PEPTIDE

R

N

N

N

N

R

R

C

TETRA-AMINE

N

C HNNHN

O

PEPTIDE

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+Pharmacodynamic Modifier

Radionuclide Conjugate

Activating Group

N PEPTIDEX

H

Pharmacodynamic Modifier

Radionuclide Conjugate

H2N PEPTIDE

Radiopharmaceuticals R&D Interests

99mTc-RGD Peptide

NCH3

HN

NH

O

OON

O

NH

O

OH

HN

O

N

O

H

O

NH2N

H

NH

N N

Tc

O O

S S

O

99mTc-analogue of GPIIb/IIIa receptor antagonist for thrombus imaging.

METALS IN MEDICINE

METALS IN MEDICINE

Apoptosis

Angiogenesis (v3 antagonists, MMP’s)

Growth factors (VEGF, EGF) Receptor-based Tumour targeting (Breast,

Melanoma and Prostate) Peptides Cell labelling-proteomics

Radiopharmaceuticals R&D Interests

Radiotherapy

External beam

Brachytherapy (Radioactive implants)

Restenosis

Particulates (Sirtex-spheres)

Systemic -Radionuclide Therapy (Zevalin-Lymphoma)

METALS IN MEDICINE

Systemic -Radionuclide Therapy

Non-invasive delivery of selective radiation to tumours

Combination of brachytherapy and chemotherapy

Limited toxicity- long term effects compare favourably with those of chemotherapy and external beam therapy.

Promising- Advances in molecular targeting technologies (receptors, peptides, MoAbs) and new isotopes

Synergistic effects (Molecular Inhibitors, Hypoxia, Angiogenesis, Selective Cytotoxicity

METALS IN MEDICINE

Opportunities

Improvements in targeting strategies-Selectivity and Spepcificity

Reduced Toxicity- clearance

Drug-Delivery

Radionuclide Availability and Costs

Regulatory

Medical Infrastructure

METALS IN MEDICINE