Radiosynthesis of 191Os-2-acetylpyridine thiosemicarbazone complex, as an in vivo therapeutic radionuclide generator

Document Type: Original Article

Authors

1 Nuclear Science and Technology Research Institute (NSTRI), Atomic Energy Organization of Iran (AEOI), Tehran, Iran

2 Faculty of Nuclear Engineering and Physics, Amirkabir University of Technology, Tehran, Iran

Abstract

Introduction: Due to the anti-proliferative properties of platinum group-thiosemicarbazone complexes, the production of 191Os-labeled 2-acetyl pyridine 4-N-methylthiosemicarbazone (191Os-APMTS) was investigated. Methods: [191Osmium (T½= 15.4d) was produced via the 190Os(n,γ)191Os nuclear reaction using enriched target irradiated with thermal neutrons. Reaction of in-house synthesized 2-acetylpyridine thiosemicarbazone (APMTS) with 191Os yielded [191Os]APMTS checked by ITLC followed by stability, partition co-efficient and biodistribution determination. Results: Following synthesis and spectroscopic determination of the ligand (>99% chemical purity), the complex was prepared with a radiochemical purity of more than 95% (RTLC) and specific activity of 21.5 GB/mM and was stable in the formulation and presence of human serum at 37°C for up to 48h. The partition coefficient was determined (log P. 1.23). The biodistribution study up to 4 days demonstrated significant tissue uptake differences in the bone, blood, heart and thyroid. Conclusion: This is the first Os-191 labeled thiosemicarbazone designed as an in-vivo therapeutic radionuclide generator. Further investigation is ongoing on the evaluation of the complex in tumor bearing animals.

Keywords

Main Subjects


Belicchi-Ferrari M, Bisceglie F, Casoli C, Durot S, Morgenstern-Badarau I, Pelosi G, Pilotti E, Pinelli S, Tarasconi P. Copper(II) and cobalt(III) pyridoxal thiosemicarbazone complexes with nitroprusside as counterion: syntheses, electronic properties, and antileukemic activity. J Med Chem. 2005 Mar 10;48(5):1671-5.

Hall IH, Lackey CB, Kistler TD, Durham RW Jr, Jouad EM, Khan M, Thanh XD, Djebbar-Sid S, Benali-Baitich O, Bouet GM. Cytotoxicity of copper and cobalt complexes of furfural semicarbazone and thiosemicarbazone derivatives in murine and human tumor cell lines.  Pharmazie. 2000 Dec;55(12):937-41.

Miller MC 3rd, Stineman CN, Vance JR, West DX, Hall IH. The cytotoxicity of copper(II) complexes of 2-acetyl-pyridyl-4N-substituted thiosemicarbazones. Anticancer Res. 1998 Nov-Dec;18(6A):4131-9.

Finch RA, Liu MC, Cory AH, Cory JG, Sartorelli AC. Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone; 3-AP): an inhibitor of ribonucleotide reductase with antineoplastic activity. Adv Enzyme Regul. 1999;39:3-12.

Pal I, Basuli F, Bhattacharya S. Thiosemicarbazone complexes of the platinum metals. A story of variable coordination modes. Proc Indian Acad Sci. (Chem Sci.) 2002;114(4):255-268.

Ni WX, Man WL, Cheung MT, Sun RW, Shu YL, Lam YW, Che CM, Lau TC. Osmium(VI) complexes as a new class of potential anti-cancer agents. Chem Commun (Camb). 2011 Feb 21;47(7):2140-2.

Büchel GE, Stepanenko IN, Hejl M, Jakupec MA, Arion VB, Keppler BK. [Os(IV)Cl(5)(Hazole)](-) complexes: synthesis, structure, spectroscopic properties, and antiproliferative activity. Inorg Chem. 2009 Nov 16;48(22):10737-47.

Hanif M, Nazarov AA, Hartinger CG, Kandioller W, Jakupec MA, Arion VB, Dyson PJ, Keppler BK. Osmium(II)--versus ruthenium(II)--arene carbohydrate-based anticancer compounds: similarities and differences. Dalton Trans. 2010 Aug 21;39(31):7345-52.

van Rijt SH, Peacock AF, Johnstone RD, Parsons S, Sadler PJ. Organometallic osmium(II) arene anticancer complexes containing picolinate derivatives. Inorg Chem. 2009 Feb 16;48(4):1753-62.

Bergamo A, Masi A, Peacock AF, Habtemariam A, Sadler PJ, Sava G. In vivo tumour and metastasis reduction and in vitro effects on invasion assays of the ruthenium RM175 and osmium AFAP51 organometallics in the mammary cancer model. J Inorg Biochem. 2010 Jan;104(1):79-86.

Jalilian AR, Mehdipour P, Akhlaghi M, Yousefnia H, Shafaii K. Evaluation of a [67Ga]-thiosemicarbazone complex as tumor imaging agent. Sci Pharm.  2009;77; 343–354.

Jalilian AR, Haghighi Moghadam F, Nemati A, Abedini M. Development of [67Ga]2-acetylpyridine 4,4-dimethyl thiosemicarbazone for detection of malignancies. J Label Compound Radiopharm. 2007;50:414-15.

Lewis JS, Sharp TL, Laforest R, Fujibayashi Y, Welch MJ. Tumor uptake of copper-diacetyl-bis(N(4)-methylthiosemicarbazone): effect of changes in tissue oxygenation. J Nucl Med. 2001 Apr;42(4):655-61.

Jalilian AR, Sadeghi M, Yari-Kamrani Y, Ensaf MR. Development of [103Pd]-2-acetylpyridine 4 N -methyl thiosemicarbazone complex for targeted therapy. J Radioanal Nucl Chem. 2006; 268(3):605-11.

Jalilian AR, Rowshanfarzad P, Sabet M, Shafiee A. Preparation of [61Cu]-2-acetylpyridine thiosemicarbazone complex as a possible PET tracer for malignancies. Appl Radiat Isot. 2006 Mar;64(3):337-41.

Brihaye C, Butler TA, Knapp FF Jr, Guillaume M, Watson EE, Stabin MG. A new osmium-191/iridium-191m radionuclide generator system using activated carbon. J Nucl Med. 1986 Mar;27(3):380-7.

Salek N, Jamre M, Jalilian AR, Shamsaee M. Feasibility and improvement in production of 191Os/ 191mIr generator by Tehran Research Reactor (TRR). Ann Nucl Energ. 2012;40(1):194-99.

Gingras BA, Suprunchuk T, Bayley CH. The preparation of some thiosemicarbazones and their copper complexes: Part III. Can J Chem. 1962;40(6):1053-57.

Jalilian AR, Rowshanfarzad P, Sabet M. Preparation of [61Cu]Pyruvaldehyde-bis (N4-methylthiosemicarbazone) Complex as a Possible PET Radiopharmaceutical. Radiochimica Acta. 2006;94(2):113–17.

Kairemo KJ, Kestilä MS, Svahn RI, Hiltunen JV. 191mIr: distribution and retention in animal experiments. Nuklearmedizin. 1995 Jun;34(3):115-7.