Development of Fluorine-18-Labeled 5-HT_1AAntagonists

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.

Experiment assessment of mass effects in the rat: implications for small animal PET imaging

“…Furthermore, the equations used here and those used by Hume et al [19] and Meikle et al [24] are equilibrium equations and there is no indication that FCWAY is at steady state in all tissues at 30 min after injection although the net eff ux is similar in target tissue and metabolite corrected plasma [9]. In conclusion, small differences can change the percentage saturation substantially and experiments must be performed for each radiopharmaceutical at the injected dose and specif c activity.…”

An automated one-step one-pot [18F]FCWAY synthesis: development and minimization of chemical impurities

“…[ 18 F]FCWAY was initially developed in our laboratories using a multiple step synthetic sequence [1]. This radiopharmaceutical has been applied to human clinical trials in several protocols exploring the involvement of 5-HT 1A receptors in neurophysiologic and neuropsychiatric disorders.…”

“…The FCWAY reference standard sample for QC analysis was prepared as a custom synthesis reported previously [1]. Most other chemicals were purchased from commercial suppliers and used as they were received.…”

“…cis Pentamethylbenzyl 4-acetoxycyclohexanecarboxylate (2)-To 3.0 g (10 mmol) of cis pentamethylbenzyl 4-hydroxycyclohexanecarboxylate prepared according to previously published procedure [1] was added 40 mL CH 2 Cl 2 , 1.4 mL of acetyl chloride and 1.4 mL of triethylamine. The mixture was refluxed overnight.…”

Assessment of labelled products with different radioanalytical methods: study on 18F-fluorination reaction of 4-[18F]fluoro-N-[2-[1-(2-methoxyphenyl)-1-piperazinyl]ethyl-N-2-pyridinyl-benzamide (p-[18F]MPPF)

“…However, Mass Spectrometry (MS) may solve this problem, being a more sensitive tool for qualitative analyses of radiopharmaceuticals [3][4][5]. [6,7], [ 18 F]FBWAY [8] and 18 F-mefway [9] have been reported in the literature. Production of p-[…”