Synthesis, Ex Vivo Evaluation, and Radiolabeling of Potent 1,5-Diphenylpyrrolidin-2-one Cannabinoid Subtype-1 Receptor Ligands as Candidates for In Vivo Imaging.

[摘要]：(Heterocyclic Compounds (One Hetero Atom)) Section We have reported that [methyl-11C] (3R,5R)-5-(3-methoxyphenyl)-3-[(R)-1-phenylethylamino]-1-(4-trifluorom ethylphenyl)pyrrolidin-2-one (I, R = OC11H3) binds with high selectivity to cannabinoid type-1 (CB1) receptors in monkey brain in vivo. We now describe the synthesis of I (R = OCH3) and four analogs, namely, the 4-fluorophenyl, 3-fluoromethoxy, 3-fluoromethoxy-d2, and 3-fluoroethoxy analogs, and report their activity in an ex vivo model designed to ligands. These ligands exhibited high, selective potency at CB1 receptors in vitro (Kb < 1 nM). Each ligand (30 mg/kg, iv) was injected into rats under baseline and pretreatment conditions and quantified at later times in frontal cortex ex vivo with liq. chromatog.-mass spectrometry (LC-MS) detection. Maximal ligand uptakes were high (22.6-48.0 ng/g). Under pretreatment, maximal brain uptakes were greatly reduced (6.5-17.3 ng/g). Since each ligand readily entered brain and bound with high selectivity to CB1 receptors, we then as well as other [11C]- and [18F]-labeled ligands in adequate activities for evaluation as candidate PET radioligands in vivo.

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