title: Labeling and evaluation of N-[11C]methylated quinoline-2-carboxamides as potential radioligands for visualization of peripheral benzodiazepine receptors.
abstract: The novel quinoline-2-carboxamide derivatives N-[methyl-11C]-3-methyl-4-phenyl-N-(phenylmethyl)quinoline-2-carboxamide ([11C]4), (+/-)-N-[methyl-11C]-3-methyl-N-(1-methylpropyl)-4-phenylquinoline-2-carboxamide ([11C]5), and (+/-)-N-[methyl-11C]-3-methyl-4-(2-fluorophenyl)-N-(1-methylpropyl)quinoline-2-carboxamide ([11C]6) were labeled with carbon-11 (t1/2 = 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 [11C]methyl iodide or [11C]methyl triflate in the presence of tetrabutylammonium hydroxide or potassium hydroxide in dimethylformamide. The radioligands [11C]4, [11C]5, and [11C]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/micromol 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 PBR of [11C]4, [11C]5, and [11C]6 in heart, lung, kidney, adrenal gland, spleen, and brain. The biological data suggest that [11C]5, [11C]6, and particularly [11C]4 are promising radioligands for PBR imaging in vivo with PET.
authors.affiliation: INB-CNR, University of Milano/Bicocca, Institute H.S. Raffaele, Via Olgettina 60, 20132 Milano, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Matarrese
authors.forename: R M
authors.initials: RM
authors.lastname: Moresco
authors.forename: A
authors.initials: A
authors.lastname: Cappelli
authors.forename: M
authors.initials: M
authors.lastname: Anzini
authors.forename: S
authors.initials: S
authors.lastname: Vomero
authors.forename: P
authors.initials: P
authors.lastname: Simonelli
authors.forename: E
authors.initials: E
authors.lastname: Verza
authors.forename: F
authors.initials: F
authors.lastname: Magni
authors.forename: F
authors.initials: F
authors.lastname: Sudati
authors.forename: D
authors.initials: D
authors.lastname: Soloviev
authors.forename: S
authors.initials: S
authors.lastname: Todde
authors.forename: A
authors.initials: A
authors.lastname: Carpinelli
authors.forename: M G
authors.initials: MG
authors.lastname: Kienle
authors.forename: F
authors.initials: F
authors.lastname: Fazio
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002250:Carbon Radioisotopes; D007553:Isotope Labeling; D008024:Ligands; D008297:Male; D008745:Methylation; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: D000577:Amides; D002250:Carbon Radioisotopes; D008024:Ligands; C421627:N-methyl-3-methyl-4-(2-fluorophenyl)-N-(1-methylpropyl)quinoline-2-carboxamide; C421625:N-methyl-3-methyl-4-phenyl-N-(phenylmethyl)quinoline-2-carboxamide; C421626:N-methyl-3-methyl-N-(1-methylpropyl)-4-phenylquinoline-2-carboxamide; D011804:Quinolines; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A