Radiosynthesis and evaluation of an ~(18)F-labeled positron emission tomography (PET) radioligand for brain histamine subtype-3 receptors based on a nonimidazole 2-aminoethylbenzofuran chemotype

摘要

A known chemotype of H _3 receptor ligand was explored for development of a radioligand for imaging brain histamine subtype 3 (H _3) receptors in vivo with positron emission tomography (PET), namely nonimidazole 2-aminoethylbenzofurans, represented by the compound (R)-(2-(2-(2-methylpyrrolidin-1-yl)ethyl)benzofuran-5-yl)(4-fluorophenyl) methanone (9). Compound 9 was labeled with fluorine-18 (t _(1/2) = 109.7 min) in high specific activity by treating the prepared nitro analogue (12) with cyclotron-produced [~(18)F]fluoride ion. [~(18)F]9 was studied with PET in mouse and in monkey after intravenous injection. [~(18)F]9 showed favorable properties as a candidate PET radioligand, including moderately high brain uptake with a high proportion of H _3 receptor-specific signal in the absence of radiodefluorination. The nitro compound 12 was found to have even higher H _3 receptor affinity, indicating the potential of this chemotype for the development of further promising PET radioligands.