F-18-Labelled Metomidate Analogues As Adrenocortical Imaging Agents

Introduction: Two- and one-step syntheses of F-18-labelled analogues of metomidate, such as 2-[F-18]fluoroethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (1), 2-[F-18]fluoroethyl 1-[(1R)-1-(4-chlorophenyl)ethyl]-1H-imidazole-5-carboxylate (2), 2-[F-18]fluoroethyl 1-[(1R)1-(4-bromophenyl)ethyl] 1H-imidazole-5-carboxylate (3), 3-[F-18]fluoropropyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (4) and 3-[F-18]fluoropropyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (5) are presented.Methods: Analogues 1-5 were prepared by a: two-step reaction sequence that started with the synthesis of either 2-[F-18]fluoroethyl 4-methylbenzenesulfonate or 3-[F-18]fluoropropyl 4-methylbenzenesulfonate. These were used as F-18-alkylating agents in the second step, in which they reacted with the ammonium salt of a 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylic acid. One-step-labelling syntheses of 1, 2 and 5 wen, also explored. Analogues 1-4 were biologically validated by frozen-section autoradiography and organ distribution. Metabolite analysis was performed for 2 and 3.Results: The radiochemical yield of the two-step synthesis was in the range of 10-29% and that of the one-step synthesis was 25-37%. Using microwave irradiation in the one-step synthesis of 1 and 2 increased the radiochemical yield to 46 3% and 79 30%, respectively.Conclusion: Both the frozen-section autoradiography and organ distribution results indicated that analogue 2 has a potential as an adrenocortical imaging agent, having the highest degree of specific adrenal binding and best ratio of adrenal to organ uptake among the compounds studied. (C) 2009 Elsevier Inc. All rights reserved.