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
METALS IN MEDICINE
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
METALS IN MEDICINE
+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
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