Based on our preclinical studies in rodents and monkeys, which sup-port our hypothesis that F-18 fluoropropy-TZTP is an M2 selective ligand, we have filed an Investigational New Drug (IND) application and proceeded to a Phase II human study in collaboration with NIA and NIMH. Twelve normal subjects have been studied to date with results consistent with M2 receptor binding. Distribution volume (V) values, represent-ing total tissue binding, were very similar in cortical regions, basal ganglia, and thalamus (35?7, 36?10, and 31?7 ml/ml, respectively), but were significantly higher (p<.01) in amygdala (47?12 ml/ml). We have also developed a series of F-18 and C-11-labeled antagonists for the 5HT1A and 5HT2A receptor. We have synthesized five fluorinated derivatives of WAY 100635, N-{2-(4-(2-methoxyphenyl)-piperazino)ethyl}- N-(2-pyridyl) cyclohexanecarboxamide using various acids in place of the cyclohexanecarboxylic acid (CHCA) in the reaction scheme. The five acids are 4-fluorobenzoic acid (FB), 4-fluoro-3-methylbenzoic acid (MeFB) trans-4-fluorocyclohexanecarboxylic acid (FC), 4- fluoromethylbenzoic acid (FMeB) and 3-nitro-4-fluoromethylbenzoic acid (NFMeB). These compounds were radiolabeled with F-18, and their biological properties were evaluated in rats and compared with those of [C-11]carbonyl WAY 100635 ([carbonyl-C-11]4a). [Carbonyl-C-11]4a cleared the brain with a biological half life averaging 41 min. The metabolite-corrected blood radioactivity had a half life of 29 min. [F- 18]FCWAY ([F-18]4d) gave half lives and intercepts comparable to [carbonyl-C-11]4a in the brain, but the blood clearance was faster. [F- 18]FBWAY ([F-18]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[F-18]FBWAY ([F-18]4c) were 16 min and 18 min, respectively. For each 1999 Annual Report of Research Activities compound, the corresponding carboxylic acid was identified as a metabolite in blood. Fluoride was also found after injection of [F- 18]4d. However, for all compounds there was a good correlation (R greater than 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 concentra-tion of receptors as determined by in vitro quantitative autoradiography in rat. Specific bind-ing ratios [region of interest (ROI)/Cerebellum-1] in control studies for cortex (Ctx) and hippocampus (H) were higher for [carbonyl-C-11]4a and [F-18]4d compared to [F-18]4b and [F-18]4c. [F-18]4d has similar pharmacokinetic properties and comparable specific binding ratios to [carbonyl-C-11]4a. Fifty nmol of 4a blocked only 30 percent of the spe-cific binding of [F-18]4d while complete blockade was obtained from co-injection of 200 nmol of 4a (H/Cb-1 from 17.2 to 0.6). [F-18]4b and [F-18]4c showed lower specific bind-ing ratios than [carbonyl-C-11]4a and [F-18]4d. [F- 18]4c was superior to [F-18]4b since its specific binding was more readily blocked by 4a. These studies suggest that [F-18]4c should be a useful compound to assess dynamic changes in serotonin levels while [F- 18]4d, with its high contrast and F-18 label, should provide better statistics and quantification for static measurement of 5-HT1A receptor distribution. We have also evaluated [C-11]MDL 100,907 as a tracer for 5-HT2A receptors in primates, developed a tracer kinetic model for quantification, and developed an optimized strategy and various model- based methods for the measurement of neurotransmitter release with [C- 11] raclopride. Longer-lived PET radionuclides are also under development. We are producing Ga-66, Tc-94m, and Br-76 and have signed a CRADA to develop a procedure to produce I-124. Tc-94m has been produced using enriched molybdenum oxide and used to produce four radiopharmaceuticals, Tc-94m DTPA, Tc-94m TRODAT1, Tc-94m Sestamibi, and Tc-94m Arcitumomab. The production yields at 13.8 MeV protons on enriched Mo results in more than 10 percent Tc-94 and lesser amounts of Tc-93 and Tc-95 compared to the yield of Tc-94m. Images obtained using a GE Advance in two-dimensional mode demonstrated the sensitivity and resolution of this PET radionuclide. We also continue to produce At-211 for use in alpha particle therapy.
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