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

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• 作者：Sean R. Donohue ; Joseph H. Krushinski ; Victor W. Pike ; Eyassu Chernet ; Lee Phebus ; Amy K. Chesterfield ; Christian C. Felder ; Christer Halldin ; John M. Schaus
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：September 25, 2008
• 年：2008
• 卷：51
• 期：18
• 页码：5833-5842
• 全文大小：265K
• 年卷期：v.51,no.18(September 25, 2008)
• ISSN：1520-4804

文摘

We have reported that [methyl-¹¹C] (3R,5R)-5-(3-methoxyphenyl)-3-[(R)-1-phenylethylamino]-1-(4-trifluoromethylphenyl)pyrrolidin-2-one ([¹¹C]8, [¹¹C]MePPEP) binds with high selectivity to cannabinoid type-1 (CB₁) receptors in monkey brain in vivo. We now describe the synthesis of 8 and four analogues, namely, the 4-fluorophenyl (16, FMePPEP), 3-fluoromethoxy (20, FMPEP), 3-fluoromethoxy-d₂ (21, FMPEP-d₂), and 3-fluoroethoxy analogues (22, FEPEP), and report their activity in an ex vivo model designed to identify compounds suitable for use as positron emission tomography (PET) ligands. These ligands exhibited high, selective potency at CB₁ receptors in vitro (K_b < 1 nM). Each ligand (30 μg/kg, iv) was injected into rats under baseline and pretreatment conditions (3, rimonabant, 10 mg/kg, iv) and quantified at later times in frontal cortex ex vivo with liquid chromatography-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 established and here describe methods for producing [¹¹C]8, [¹¹C]16, and [¹⁸F]20−22 in adequate activities for evaluation as candidate PET radioligands in vivo.