title: Development of fluorine-18-labeled 5-HT1A antagonists.
abstract: We have synthesized five fluorinated derivatives of WAY 100635, N-{2-[4-(2-methoxyphenyl)piperazino]ethyl}-N-(2-pyridyl)cyclohe xaneca rboxamide (4a), using various acids in place of the cyclohexanecarboxylic acid (CHCA, 2a) in the reaction scheme. The five acids are 4-fluorobenzoic acid (FB, 2b), 4-fluoro-3-methylbenzoic acid (MeFB, 2c), trans-4-fluorocyclohexanecarboxylic acid (FC, 2d), 4-(fluoromethyl)benzoic acid (FMeB, 2e), and 3-nitro-4-(fluoromethyl)benzoic acid (NFMeB, 2f) (see Scheme 1). These compounds were radiolabeled with fluorine-18, and their biological properties were evaluated in rats and compared with those of [11C]carbonyl WAY 100635 ([carbonyl-11C]4a). [Carbonyl-11C]4a cleared the brain with a biological half-life averaging 41 min. The metabolite-corrected blood radioactivity had a half-life of 29 min. [18F]FCWAY ([18F]4d) gave half-lives and intercepts comparable to [carbonyl-11C]4a in the brain, but the blood clearance was faster. [18F]FBWAY ([18F]4b) showed an early rapid net efflux from the whole brain, clearing with a biological half-life of 35 min. The metabolite-corrected blood half-life was 41 min. The comparable whole brain and blood half-lives for Me[18F]FBWAY ([18F]4c) were 16 and 18 min, respectively. For each compound, the corresponding carboxylic acid was identified as a major metabolite in blood. Fluoride was also found after injection of [18F]4d. However, for all compounds there was a good correlation (R > 0.97) between the differential uptake ratio (DUR, (%ID/g) x body weight (g)/100) in individual rat brain regions at 30 min after injection and the concentration of receptors as determined by in vitro quantitative autoradiography in rat. Specific binding ratios [region of interest (ROI)/cerebellum-1] in control studies for cortex (Ctx) and hippocampus (H) were higher for [carbonyl-11C]4a and [18F]4d compared to [18F]4b and [18F]4c. [18F]4d has similar pharmacokinetic properties and comparable specific binding ratios to [carbonyl-11C]4a. Fifty nanomoles of 4a blocked only 30% of the specific binding of [18F]4d, while complete blockade was obtained from co-injection of 200 nmol of 4a (H/Cb-1 from 17.2 to 0.6). [18F]4b and [18F]4c showed lower specific binding ratios than [carbonyl-11C]4a and [18F]4d. [18F]4c was superior to [18F]4b since its specific binding was more readily blocked by 4a. These studies suggest that [18F]4c should be a useful compound to assess dynamic changes in serotonin levels while [18F]4d, with its high contrast and F-18 label, should provide better statistics and quantification for static measurement of 5-HT1A receptor distribution.
authors.affiliation: Positron Emission Tomography Department, Clinical Center, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
authors.forename: L
authors.initials: L
authors.lastname: Lang
authors.forename: E
authors.initials: E
authors.lastname: Jagoda
authors.forename: B
authors.initials: B
authors.lastname: Schmall
authors.forename: B K
authors.initials: BK
authors.lastname: Vuong
authors.forename: H R
authors.initials: HR
authors.lastname: Adams
authors.forename: D L
authors.initials: DL
authors.lastname: Nelson
authors.forename: R E
authors.initials: RE
authors.lastname: Carson
authors.forename: W C
authors.initials: WC
authors.lastname: Eckelman
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism; D005462:Fluorine Radioisotopes; D007553:Isotope Labeling; D008024:Ligands; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D001549:Benzamides; D005462:Fluorine Radioisotopes; D008024:Ligands; D010879:Piperazines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide