Based on our preclinical studies in rodents and monkeys, which support our hypothesis that F-18 fluoropropylthio-TZTP is an M2 selective ligand, we have filed an Investigational New Drug application (IND) and proceeded to a Phase II human study in collaboration with NIA and NIMH. Five normal subjects have been studied to date with results consistent with M2 receptor binding.We have also developed a series of 18F and 11C labeled antagonists for the 5HT1A and 5HT2A receptor. The compounds tested have high specificity for the receptor class and high receptor specificity for the receptor subtype. Distribution studies in vivo are consistent with 5HT receptor binding. We have chosen for further evaluation two derivatives of WAY 100635 [(N-(2-(1-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl) cyclohexane-carboxamide] by replacing the cyclohexane carboxylic acid with either 3-methyl, 4-fluorobenzoic acid (to produce MeFBWAY) or trans 4-fluorocyclohexylcarboxylic acid (to produce FCWAY). MeFBWAY has an inhibition constant of 4 nM, has high brain uptake in rats, and a low non-specific binding fraction. In monkeys, [18F]MeFBWAY approaches transient equilibrium rapidly in all tissues. Because of its rapid kinetics, [18F]MeFBWAY can be infused to equilibrium and readily displaced by an injection of 20 nmol/Kg WAY. Because of the lower Ki, lower contrast is achieved when compared to the higher affinity compound [18F]FCWAY. In monkey studies, transient equilibrium was achieved only by 2 hours after injection of [18F]FCWAY. The regional specific binding pattern was highly correlated with that observed with the parent compound, WAY 100635 and pre- and post-injection of WAY 100635 after injection of [18F]FCWAY confirmed saturable binding. All preclinical work is completed on both compounds. [18F]FCWAY is better suited for the measurement of receptor concentration changes. Whereas, [18F]MeFBWAY is better suited to measure displacement due to changes in endogenous neurotransmitter.We have also done the following:Y Evaluated [C-11]MDL 100,907 as a tracer for 5-HT2A receptors in primates and developed a tracer kinetic model for quantification.Y Developed an optimized strategy and various model-based methods for the measurement of neurotransmitter release with [11C] raclopride.Y Evaluated the brain kinetics of 3 [18F]-labeled acids that are metabolites of the 5HT1A tracers.We have found that an infusion of lysine (Aminosyn II) decreases the residence time of [18F] radiolabeled antiTAC dsFv (a fragment with high affinity for the IL-2a receptor) in the baboon kidney by altering the pharmacokinetics by preventing uptake. This will reduce the absorbed radiation dose to the kidney, thereby permitting larger injected doses in human subjects.Longer lived PET radionuclides are also under development. We are producing Ga-66, Tc-94m, and have signed a CRADA to develop a procedure to produce I-124. The Ga-66 is a long-lived positron emitter (T1/2=9.4 h) useful for labeling antibody fragments and low molecular weight proteins. Tc-94m (T1/2=52.5 min) is being used in place of Tc-99m in the traditional nuclear medicine kits to produce a myocardial imaging agent and a tumor imaging agent for PET. We also continue to produce At-211 for use in alpha particle therapy.
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