Labeling and evaluation of N-[11C]methylated quinoline-2-carboxamides as potential radioligands for visualization of peripheral benzodiazepine receptors

The novel quinoline-2-carboxamide derivatives N-[methyl-C-11]-3-methyl-4-phenyl-N-(phenyl-methyl)quinoline-2-carboxamide ([C-11]4), (+/-)-N-[methyl-C-11]-3-methyl-N-(1-methylpropyl)-4- phenylquinoline-2-carboxamide ([C-11]5), and (+/-)-N-[methyl-C-11]-3-methyl-4-(2-fluorophenyl)-N-(1-methylpropyl)quinoline-2-carboxamide ([C-11]6) were labeled with carbon-11 (t(1/2) = 20.4 min, beta (+) = 99.8%) as potential radioligands for the noninvasive assessment of peripheral benzodiazepine type receptors (PBR) in vivo with positron emission tomography (PET). The radiosynthesis consisted of N-methylation of the desmethyl precursors 3-methyl-4-phenyl-N-(phenylmethyl)quinoline-2-carboxamide (4a), (+/-)-3-methyl-N-(1-methylpropyl)-4-phenylquinoline-2-carboxamide (5a), and (+/-)-4-(2-fluorophenyl)-3-methyl-N-(1-methylpropyl)quinoline-2-carboxamide (6a) with either [C-11]methyl iodide or [C-11]methyl triflate in the presence of tetrabutylammonium hydroxide or potassium hydroxide in dimethylformamide. The radioligands [C-11]4, [C-11]5, and [C-11]6 were synthesized with over 99% radiochemical purity in 30 min, 30 +/- 5% radiochemical yield, calculated at the end of synthesis (EOS) non-decay-corrected, and 2.5 +/- 1.2 Ci/mu mol of specific radioactivity. Inhibition studies in rats following intravenous pre-administration of 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK 11195, 1) showed high specific binding to PER of [C-11]4, [C-11]5, and [C-11]6 in heart, lung, kidney, adrenal gland, spleen, and brain. The biological data suggest that [C-11]5, [C-11]6, and particularly [C-11]4 are promising radioligands for PER imaging in vivo with PET.