Quality Systems Personnel Training Program (QSPTP) Radiometal Overview PDF

General Overview of Radiometals Cathy S. Cutler Brookhaven National Laboratory  Imaging Modalities Radioactive Non-Radioactive Gamma scintigraphy Magnetic Resonance (MR) (111In, 99mTc, etc.) (Gd, Fe, etc.) Po...

General Overview of Radiometals Cathy S. Cutler Brookhaven National Laboratory  Imaging Modalities Radioactive Non-Radioactive Gamma scintigraphy Magnetic Resonance (MR) (111In, 99mTc, etc.) (Gd, Fe, etc.) Positron Emission Tomography Optical (PET) (near-IR dyes, (18F, 11C, 64Cu, 86Y, etc.) Eu luminescence, etc.) Metals Play important roles in molecular imaging! Feature an impressive range of half-lives Compatible with a wide range of chemistries for incorporation into biomolecules  Radiotracer Radionuclide or radioactivity labeled molecular entity Designed to trace in vitro and in vivo biochemical cellular, and physiological processes when used for biomedical or medical applications A true radiotracer will not alter biochemical reactions or elicit pharmacologic effects because of its very small mass.* *This is not always feasible or necessary for developing effective molecular imaging applications. Things to Consider Chemistry of the metal Formulation of the complex Stabilization for ultimate use Choice of Radionuclide Physical decay characteristics - mode of decay, half-life, purity, specific activity Availability - reliability, quality, scale, cost Radiolabeling chemistry simplicity, stability, pharmacokinetics Types of Radiation  particle—He2+ nucleus  beta particle—e- ejected by nucleus + positron—e+ ejected by nucleus Undergoes annihilation to emit two 0.511 MeV photons at 180o  gamma ray—photon emitted by nucleus Diagnosis Purpose is imaging disease or function Need penetrating radiation – Gamma or positron emission Examples: 99mTc, 111In, 123I, 18F Radiotherapy Purpose is cell destruction Particle emitters –  particles –  particles – Auger electrons Examples: 153Sm, 90Y, 177Lu, 213Bi What Is Important In Choosing an Isotope for Radiotherapy? - I Type and energy of emissions [alpha, beta, Auger electrons, low energy gammas, etc.] Half-life – Matched to uptake and clearance of agent – Affects ease [feasibility!] of transport from production site Specific Activity – High is not always desirable! Type of production and availability of target material What Is Important In Choosing an Isotope for Radiotherapy? - II Chemistry/Radiochemistry of the isotope – Determines ease of labeling and stability of labeled agent [Re-186 vs. Y-90] – Affects in-vivo clearance characteristics of radioisotope [e.g., Re-186 clearance by re-oxidation to perrhenate] – Affects separation and purification from target A Schematic Comparison of Energy Types for Therapeutic Radionuclides S.C. Srivastava Semin Nucl Med 42:151-163, 2012 11 12 Non-metallic isotopes Advantages Can be incorporated into the molecule Little to no impact on the pharmacokinetics Short half-lives Disadvantages Half-lives to short for macromolecular biotargeting agents Demanding and complex synthesis often multiple-steps Chemistry not compatible with sensitive biomolecular targeting agents Can be difficult to stabilize Lack of versatility 13 Radiometals Advantages Longer half-lives Generator availability Chelator incorporation Radiolabeling compatible for biomolecules Diversity Disadvantages Can alter the biodistribution Radiolabeling not always suitable for biomolecules Impurities can impact radiolabeling, biodistribution or use Availability 14 Mechanisms of Delivery Bare radionuclide I-131, Sr-89 Seeds or particles Pd-103, Ir-192 Small molecules Sm-153, Ho-166 Molecular targeting agents Y-90, I-131 Nanoparticles Au-198, Ac-225 15  Targeting vector (peptide, mAb, hormone, etc) Radionuclide Bifunctional chelating agent (BFCA) Linker or spacer M Radiometal Bifunctional Linker Targeting Chelating Vector Agent Diagnostic agents - identify the disease - emit a photon or gamma ray Therapeutic agents - treat specific diseases - emit particles (beta, alpha, conversion electrons, Auger electrons, etc) Metal Considerations Ligand or chelate Metal ion specific Hard-soft acid-base considerations Hard: O, N, F, Cl Soft: S, P, CO, I Kinetic and thermodynamic stability Large Kf and small koff koff most important in vivo Oxidation state of metal ion For Tc/Re -1 to +7 known Redox stability of the metal ion Radiometal Labeling Chemistry Simple and Easy Typically one-step labeling to final product Optimized for pH, heating, time Radiometal agents stabilized with antioxidants for shipping to remote locations, even overseas (e.g. Lutathera shipped from Italy to the US) Tc-99m agents produced by kit formulation with precursor and reducing agents in one step Amount of precursor in final product is very low, and high molar activity achieved (pmol to nmol of unlabeled compound) Radiometal Considerations Radiotracer concentrations Hydrolysis to M(OH)x Adsorption to surfaces Minor impurities All reactants in large excess over radiometal concentration, especially if “no carrier added” Labeled vs unlabeled chelate Stability to exchange with potential ligands in vivo Glutathione, transferrin, etc. Trace oxygen Isotope Pairs Therapeutic Isotope Imaging “Surrogate(s)” 131I (t1/2 = 8d) 124/123I 90Y (t1/2 = 2.7d) 86Y/111In/68Ga/89Zr 177Lu (t1/2 = 6.7d) 111In/68Ga/89Zr/44/43Sc 186Re (t1/2 = 3.7d) 99mTc 77Br (t1/2 = 2.4 d) 76Br 67Cu (t1/2 = 2.6 d) 64Cu Isotope Pairs Therapeutic Isotope Imaging “Surrogate(s)” 47Sc (t1/2 = 3.35d) 44/43Sc 225Ac (t1/2 = 10d) 86Y/111In/68Ga/89Zr/ 44/43Sc/134Ce(134La)/132La 77As (t1/2 = 38.83 hr) 72As 161Tb (t1/2 = 6.9d) 155Tb/152Tb 227Th (t1/2 = 18.72 d) 89Zr, 134Ce(134La) 212Pb (t1/2 = 10 hr) 210Pb 22 Isotope Pairs: Considerations May or may not be the same element Chemistry/Structural variations → Biology variations Varying Half-life Usually imaging surrogate has shorter half-life Can you image for as long as the therapeutic isotope is contributing dose? Do you need to? Availability A Somatostatin Analogue (Target Vector) Octreotide - marketed as Sandostatin® – Cyclic octapeptide » β-turn with Trp and Lys » D amino acids » C-terminal alcohol – Metabolically stable (plasma half-life 90-120 min) – High affinity to Sstr2 – Used as chemotherapeutic agent (e.g., to control hormonal symptoms in patients with neuroendocrine tumors) Integrated Approach Metal incorporated directly into disulfide bridge Useful for metals (M) with high affinity for S and N (i.e., Tc and Re) Typical Ligands that Bind metals HOOC COOH HOOC COOH N N N N N HOOC COOH HOOC COOH COOH EDTA DTPA HOOC COOH HOOC COOH N N N N N N N N HOOC COOH HOOC COOH DOTA TETA One compound for many radiometals Using somatostatin analogs as an example HO OH OH O N N O O N N O O H H N N HO N N H H NH O O O S S HN O H H N N HO N H O NH2 O HO HO DOTATOC Tyr(3) and C-terminal alcohol 111In, 90Y DOTATATE 67Ga, 68Ga, 64Cu, 177Lu, Tyr(3) and C-terminal carboxylic acid 225Ac DOTA-TOC: somatostatin receptor ligand for many radiometals (imaging and therapy) H. Maecke et al. O HO2C C DPhe tumor Cys uptake Tyr Has been radiolabeled with many N N 35 DTrp S S radiometals, including: In-111-OctreoScan N N In-111-DOTATOC HO2C CO2H 30 Lys Cys Thr Y-90-DOTATOC Thr(ol) Ga-67-DOTATOC 111In, 86/90Y, 177Lu, 67/68Ga, and 64Cu 25 DOTA-Tyr3-octreotide (DOTA-TOC) 20 % ID/g 15 10 Ga(III)-DOTA-D-Phe 6-coordinate 5 0 Y(III)-DOTA-D-Phe 1h 4h 24h 48h 8-coordinate  In Vitro Assays Thermodynamic stability Acid dissociation constants Redox challenge assays to glutathione, cysteine, thiols Serum assays Challenge to hydroxyapaptite Log P Stability over a wide pH range Receptor Affinity In Vivo assays in appropriate animal models Biodistribution studies in tumor bearing mice Comparison of DOTATOC labeled with Ga, In and 67 111 90Y to 111In-OctreoScan tumor uptake 35 In-111-OctreoScan In-111-DOTATOC 30 Y-90-DOTATOC Ga-67-DOTATOC 25 20 % ID/g 15 10 5 0 1h 4h 24h 48h Courtesy of Helmut Maecke, Ph.D., Univ of Basel, Switzerland Formulation Large batches - uniform production - few sites available - quality control - dose intensive - expensive, not cost effective - transportation Formulation Kit formulation - hospital orders the new radiopharmaceutical which consists of a kit and the radionuclide - normally labeling and Q.C. is performed at either the hospital radiopharmacy or central pharmacy - reduce the cost as have a kit with a long shelf- life and only produce and order what is used - use can be limited to sites Formulation Medium sized batches formulated at more than one site but not more than 10. Make batches either from large kits or from automated remote boxes Performed similarly to how PET radiopharmaceuticals are currently manufactured. 153Sm-EDTMP (Quadramet) for pain palliation PO 3 H 2 PO 3 H 2 N N PO 3 H 2 PO 3 H 2 + 153Sm 153Sm-EDTMP (Quadramet) [153Sm(EDTMP)(OH2)3]5- 9-coordinate 152Sm(n,γ)153Sm 46 h half-life 0.69 MeV β- (max) 103 keV γ (30%) Low specific activity  Quadramet Formulation Kit Constituents (2 vial kit): Kit 1: 35 mg/mL H8EDTMP, 1:1 Ca2+:EDTMP, pH 8.5 Kit 2: 153Sm (in HCl at pH 1) Combine kits: resultant pH =7; room temperature reaction O O P 5- O P O OH2 H2O3P PO3H2 O2 N OH2 153 Sm N N + Sm3+ OH2 N H2O3P PO3H2 O O PO2 H8EDTMP P O O Quadramet Formulation Questions: Why is the 153Sm at pH 1? Why do we need >300 EDTMP to 1 Sm3+? Why do we need 1 Ca2+ per EDTMP? Why do we not need to worry about >300 Ca2+ per Sm3+? Future Perspectives Cost-efficient availability of existing and new radionuclides Cost-efficient and robust preparation of radiopharmaceuticals (kit preparation) Efficient radiolabeling procedures Theragnostic concept (matched-pair) Pre-clinical imaging tools 38 Thank You 39