- Synthesis and in vivo biodistribution of F-18 labeled 3-cis-, 3-trans-, 4-cis-, and 4-trans-fluorocyclohexane derivatives of WAY 100635
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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
- Lang, Lixin,Jagoda, Elaine,Ma, Ying,Sassaman, Mark B.,Eckelman, William C.
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p. 3737 - 3748
(2007/10/03)
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- The development of additional radioligands of varying pharmacokinetics for the 5-HT1A receptor
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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.
- Lang, L.,Jagoda, E. M.,Eckelman, W. C.
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p. S21 - S23
(2007/10/03)
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- Development of fluorine-18-labeled 5-HT(1A) antagonists
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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.
- Lang, Lixin,Jagoda, Elaine,Schmall, Bernard,Vuong, Bik-Kee,Adams, H. Richard,Nelson, David L.,Carson, Richard E.,Eckelman, William C.
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p. 1576 - 1586
(2007/10/03)
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