Metals in Diagnostic and Therapeutic Radiopharmaceuticals

Metals in Diagnostic and Therapeutic Radiopharmaceuticals Silvia Jurisson Department of Chemistry, University of Missouri, Columbia, MO 21 July 2006 Radiopharmaceuticals  Drugs that contain a radioactive atom  Diagnostic imaging agents Radiotherapeutic agents  Radiopharmaceuticals  ~95% of nuclear medicine procedures are diagnostic, the rest therapeutic  Have no pharmacologic effect because at tracer levels 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  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, 131I, 213Bi, Penetration Range of Particles  Alpha particle: 30-80 m in tissue or 3-8 cell diameters  Beta particle: up to 11 mm in tissue or up to 1100 cell diameters (depends on energy) Importance of Tc-99m  Tc-99m – – – – – 6 h half-life 140 keV  emission Mo-99/Tc-99m generator High specific activity Used in >85% of all nuclear medicine scans Mo-99/Tc-99m Generator Cut away of 99Mo/99mTc generator 10.5” high 6” diameter Courtesy of Mallinckrodt Anatomic vs Physiologic Imaging Anatomic vs Physiologic Imaging SPECT Imaging of Heart Heart Agent: Tc-99m Sestamibi + O N O N N O N Tc N N O O O Cardiac Ischemia Tc-99m-sestamibi stress test Tl-201 rest Bone Agents In o rg a n ic P h o s p h a te O HO P OH O O P OH OH HO O rg a n ic P h o s p h a te s O P OH H2 C O P OH OH P yro p h o s p h a te M e th yle n e d ip h o s p h o n a te OH C CH 3 H yd ro x ye th yle n e d ip h o s p h o n a te OH C H H yd ro x ym e th yle n e d ip h o s p h o n a te Normal Canine Bone Scan Tc-99m-MDP Rib Metastasis Tc-99m-MDP Bone Scan Metastatic prostate cancer MU Research Reactor (MURR) Core The Blue Glow Therapeutic Radiometals          Rhenium-186/188 Yttrium-90 Radiolanthanides (Pm-149, Sm-153, Dy-166, Ho166, Lu-177) Rhodium-105 Copper Radioisotopes (Cu-64, Cu-67) Bismuth-212/213 Lead-212 Gold-199 Tin-117m Radionuclide Production at MURR Story of QuadraMetTM -- I  153Sm identified as a useful nuclide for radiotherapy by MU researchers 152Sm + 1n  153Sm Story of QuadraMetTM -- I  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 Disease Free Partial Response # of Dogs (%) Survival (months) 7 (18%) 25 (62%) 11 - 60 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  Sm-153-EDTMP (Quadramet) PO 3 H 2 PO 3 H 2 N N PO 3 H 2 PO 3 H 2 + 153Sm Radiopharmaceutical Design – – – – Targeting vector (peptide, mAb, hormone, etc) Radionuclide Bifunctional chelating agent (BFCA) Linker or spacer M Radiometal Bifunctional Chelating Agent Linker Targeting Vector How these work Radiopharmaceuticals – designed to take radioactive atom to in vivo targeted site (i.e., tumor receptor) radionuclide targeting compound Radiopharmaceutical Agents Injected for Delivery 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) Melanoma Imaging with Radiolabeled Peptide O AcNH S S NH H 2N Val Pro Lys O O Trp O NH Glu His DPhe Arg H 2N Val AcNH O S Re S Pro Lys O ReCCMSH O S NH Trp N O NH Glu His DPhe Arg Cyclic  -MSH (CMSH) Melanoma Imaging 8h 99mTc-CCMSH Image Targeting Vector: Bombesin Analogs Bombesin (BBN) is the amphibian analog of mammalian gastrin-releasing peptide (GRP) 1 2 3 4 4 6 7 8 9 10 11 12 13 14 pGlu-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 GRP Receptor Binding Region GRP receptors are expressed on human: Prostate Cancer Cells Pancreatic Cancer Cells Small Cell Lung Cancer Cells Breast Cancer Cells Tc-99m Analog for Breast Cancer OH O O O N O 99m NH O N H O N H O N H HN N O S H N N S Tc N H H N O O H 2N H N H N O H N O N O N H NH 2 O O 99m T c -N 3 S -5 -A v a -B B N [7 -1 4 ]N H 2 Hoffman, T. J., Simpson, S. D., Smith, C. J., Sieckman, G. L., Higginbotham, C., Volkert, W. A., Thornback, J. R. J. Nucl Med. 1999, 40, 104P. Van de Wiele, C., Dumont, F., Broecke, R. V., Oosterlinck, W. Cocquyt, V. Serreyn, R. Peers, S., Thornback, J., Slegers, G. Dierckx, R. A. Eur. J. Nucl. Med. 2000, 27, 1694-1699. 99mTc-N 3S-5-Ava-BBN(7-14)NH2 6 Hours P.I. Courtesy of C. Van de Wiele, University of Ghent Hospital, Belgium & Resolution Pharmaceuticals 02/00 Rh-105 Production 104 Ru + 1n 105 Ru +  4.4 h,  - 105 Rh Rh-105 Separation Chlorine gas HCl Trap Air NaOH trap NaOH trap Impinger Heating block Dri-bath Ru metal in NaOH Rh-105 Separation Enriched Ru-104 target dissolved in basic hypochlorite  RuO4 distilled over to HCl trap  Rh-105 containing solution acidified with HCl  Rh-105-chloride available for radiolabeling  High specific activity  Rhodium-105 35.4 hour half-life  0.566 (70%) and 0.248 (30%) MeV particles  319 keV (19%)  photon  High specific activity  Rh-105-chloride  1 Ci Rh-105: 6.8 x1015 atoms – (1.13 x 10-8 mol)  88.6 Ci/mol Rh-105 Rh(III) Chemistry  Low spin, d6 configuration – Kinetically inert  Slow to substitute – Requires alcohol (EtOH) Rh-105 Chemistry  Starting material is Rh-chloride in HCl  No carrier added concentration ~nM Work within 36 hour half-life  Hydroxymethylphosphine BFCAs O P OH OH S S OH S2P Synthesis + HS SH Br O O SH P O NaH THF O O S P O LiAlH4 S PH2 + SH O O O NaH THF O S PH2 Et2O Br OH PH2 S HO H2SO4/NaCl THF S 37% CH2O pH 8 S O OH P S OH O S Rh(III) Complexes OH OH OH OH P S S R Cl Rh C l Cl OR S Cl Cl Rh C l S R P PS2-5-Ava-BBN[7-14]NH2 H 2N O O NH O NH P OH OH NH HN N S S S NH O NH O O NH NH O O NH NH O O NH N H2 O Rh-105 Chemistry 105Rh-chloride + PS2-5-Ava-BBN[7-14]NH2 20% E tO H pH ~ 5 105 R hC l 3 (P S 2 -5-A va-B B N [7-14]N H 2 ) S2P-5-Ava-BBN[7-14]NH2  ESI-MS: m/z 1323.0 (1323.6 calc’d)  31P-NMR: 24.2 ppm  IC50: 1.21(0.10) x 10-9 M (PC-3 cells, 4oC) Normal Mouse Biodistribution Studies Rh-S2P-BBN biodistribution studies 90.00 80.00 70.00 % Dose/organ 60.00 50.00 40.00 30.00 20.00 10.00 0.00 1h 4h 24 h rin e Bl oo d Ta i H l ea rt Lu ng Li ve Sp r le St en om ac h L In Sm t I Ki nt dn e M y u Pa s cl e nc re as Bo ne Br C ai n ar ca ss organ U Pancreas Uptake (%dose/g) 14 12 10 8 6 4 2 0 1 hr 4 hr 24 hr pancreas blood kidneys PS2-8-Aoa-BBN[7-14]NH2 H 2N O O NH O NH P OH OH NH HN N S S S NH O NH O O NH NH O O NH NH O O NH N H2 O Acknowledgments Current Graduate Students Leah Arrigo Beau Ballard Yongjian Liu Sulochana Junnotula Para Kan Chandrika Somashekar Stephanie Lane Shorouk Dannoon Roderick Pomfrey Collaborators Dr. Wynn Volkert (Radiology) Dr. Mike Lewis (Vet. Med.) Dr. Tim Hoffman (Internal Med) Dr. Kattesh Katti (Physics/Radiology) Dr. Alan Ketring (MURR) Dr. Cathy Cutler (MURR) Dr. Tom Quinn (Biochemistry) Dr. C. Jeff Smith (Radiology) Dr. Susan Lever (Chemistry/MURR) Dr. John Lever (Radiology/MPP) Dr. Gary Ehrhardt (MURR) Undergraduate Students Miriam Galenas Postdoctoral Fellows Dr. Dioni Papagiannapoulou Dr. Hendrik Engelbrecht Dr. Heather Bigott Whitney Wells Nebiat Sisay Brooke Burroughs Financial Support Department of Energy NIH MURR