223699-98-7Relevant articles and documents
Synthesis and in vivo biodistribution of F-18 labeled 3-cis-, 3-trans-, 4-cis-, and 4-trans-fluorocyclohexane derivatives of WAY 100635
Lang, Lixin,Jagoda, Elaine,Ma, Ying,Sassaman, Mark B.,Eckelman, William C.
, p. 3737 - 3748 (2007/10/03)
Radioligands that are specific for the serotonin 5-HT1A receptor will be useful in characterizing the physiological action of this receptor subtype. With radioligands of varying pharmacokinetic properties, investigators can measure not only rec
The development of additional radioligands of varying pharmacokinetics for the 5-HT1A receptor
Lang, L.,Jagoda, E. M.,Eckelman, W. C.
, p. S21 - S23 (2007/10/03)
Six compounds have been prepared to further probe the structure activity relationships based on the 5-HT1A receptor ligand, WAY 100635. The goal is to obtain a series of radiotracers with varying pharmacokinetic properties. Substitution of a pyrimidine moiety, increased the specific binding ratio in the phenylcarboxamide series, but decreased the ratio in the cyclohexanecarboxamide series. A series of compounds with varying pharmacokinetic properties are now available to study a range of properties involving 5-HT1A receptor binding.
Development of fluorine-18-labeled 5-HT(1A) antagonists
Lang, Lixin,Jagoda, Elaine,Schmall, Bernard,Vuong, Bik-Kee,Adams, H. Richard,Nelson, David L.,Carson, Richard E.,Eckelman, William C.
, p. 1576 - 1586 (2007/10/03)
We have synthesized five fluorinated derivatives of WAY 100635, N-{2- [4-(2-methoxyphenyl)piperazino]ethyl)-N-(2-pyridyl)cyclohexanecarboxamide (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 [carbonyl11C]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 [carbonyl11C]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-HT(1A) receptor distribution.
