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This Article Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Seimbille, Y. Articles by Silverman, D. PubMed Articles by Seimbille, Y. Articles by Silverman, D.

Synthesis of an 18F labeled pyrazole-based Hsp90 inhibitor for PET imaging of cancers

¹ Cyclotron Unit, Dept of Radiology, University Hospital of Geneva, Geneva, Switzerland; ² Dept of Molecular & Medical Pharmacology, UCLA, Los Angeles, California

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Objectives: Over the last decade, selective small-molecule inhibitors of the Heat-Shock Protein 90 (Hsp90) have been the focus of potential therapeutics due to the pivotal role of Hsp90 in the acquisition and maintenance of each of the six "hallmarks of cancer". Our aim was therefore to develop an F-18 analogue of a pyrazole-based Hsp90-binding drug for PET imaging of cancers.

Methods: 3-(5-Chloro-2,4-dihydroxyphenyl)-N-[(4-fluorophenyl)methyl]-1H-pyrazole-4-carboxamide was prepared by: (1) coupling of 4-fluorobenzylamine with a pyrazole-4-carboxylic acid derivative; and (2) removal of the protective groups. Structure of the non-radioactive compound was established by NMR and MS. The F-18 labeled analogue of this Hsp90 ligand was subsequently prepared by a four-step radiosynthesis.

Results: 4-[18F]Fluorobenzonitrile, obtained by [18F]fluoride exchange reaction with 4-trimethylammoniumbenzonitrile triflate, was reduced with LiAlH4 to 4-[18F]fluorobenzylamine (isolated radiochemical yield = 54 ± 5%; t ~ 60 min). The latter was reacted in presence of diethyl cyanophosphonate and DIPEA with the carboxylic acid precursor. Removal of the protecting groups of the carboxamide intermediate with BCl3 in CH2Cl2 yielded, after HPLC purification, pure 3-(5-chloro-2,4-dihydroxyphenyl)-N-[(4-[18F]fluorophenyl)methyl]-1H-pyrazole-4-carboxamide (isolated radiochemical yield = 21 ± 5%; t ~ 120 min). Identity of the new radiopharmaceutical was confirmed by comparing its HPLC mobility with that of the non-radioactive analogue.

Conclusions: A new radiopharmaceutical was synthesized in amounts, times and specific activities practical for a detailed preclinical evaluation of this new F-18 labeled pyrazole-based inhibitor of Hsp90 in vitro and in animal models.

This Article Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Seimbille, Y. Articles by Silverman, D. PubMed Articles by Seimbille, Y. Articles by Silverman, D.