Summar y : Positron emISSIOn tomography and single photon emission computer tomography receptor-binding ligands can be used to measure changes in neurotransmitter levels. In particular, amphetamine-induced dopamine re lease has been assessed with P lC)raclopride by paired bolus injections and with [l 23 I]iodobenzamide by using a single bolus plus infusion (B/I) study. Here, we measured the change in P lC)raclopride-specific binding in rhesus mon keys after 4v. administration of 0.4 mg/kg amphetamine by using both the bolus and B/I paradigms. Paired bolus studies (control and postamphetamine) were analyzed us ing compartment modeling and graphical analysis with a new plasma metabolite model to measure the total distribu tion volume (VT). Specific binding, calculated with threeThe tissue concentration of receptor-binding ra diopharmaceuticals depends on many physiological parameters. A wide variety of approaches have been developed to determine parameters of neuroreceptor binding that are ideally equal or at least linearly pro portional to the free receptor concentration. These techniques include full kinetic modeling with multi ple-parameter estimation, graphical approaches that estimate one or two combined model parameters such as the total volume of distribution (VT) and simple tissue concentration ratios. With such tech niques, within-subject changes in free receptor con centration-for example, caused by an intervention

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.

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Summary:The tracer lIICj-a-methyl-L-tryptophan (aMTP) has been used to measure brain serotonin synthesis rates with positron emission tomography (PET). To address questions about the accuracy of the kinetic model, e4C]aMTP was used to directly measure conversion to C4Cj-a-methyl-serotonin (aM5HT) in monkeys that had been previously studied with PET and [1 1C]aMTP. Four male, fasted, isoflurane-anes thetized rhesus monkeys were studied with C iC]aMTP and PET. Immediately after the initial 3-hour scan, a second dose of 244sion of aMTP to aM5HT occurred; HPLC analysis of 14C radioactivity showed that greater than 96% of the total counts were in fractions corresponding to the aMTP peak. Brain con centrations of serotonin, tryptophan, 5-hydroxyindole-3-acetic acid, and aMTP also were determined f1uorometrically using external quantification. Patlak plots generated from PET im ages acquired over 3 hours showed no time period of linear increase, and final slopes were not significantly different from zero, consistent with the finding of minimal conversion to [14C]aM5HT. These data indicate that in the 3-hour period after injection, C lC]aMTP is acting predominantly as a tracer of tryptophan uptake, not serotonin synthesis.