For over fifty years, the application of tracer techniques has enhanced our understanding of biochemical and physiological processes. PET is a unique tool in tracer methodology because of its ability to track the distribution and kinetics of labeled compounds in the intact living human and animal body. The rate at which these special characteristics of PET can be applied to problems in biology and medicine is tightly coupled to the availability of biologically selective and sensitive radiotracers. This proposal, """"""""Radiotracer R & D in Nuclear Medicine and Neuroscience"""""""" focusses on radiotracer chemistry with the ultimate goal of advancing and facilitating applications in the neurosciences, in clinical practice and in drug research and development. This approach is multifaceted and synergistic, covering research in three major areas: cyclotron targetry; synthetic methodology; radiotracer biology and mechanisms. Over the past 7 year award period, we have made major advances including the first synthesis of no-carrier-added (NCA)F-18 labeled catecholamines and fluoroDOPA using a novel application of the nucleophilic aromatic substitution reaction on electron-rich aromatic rings; the first use of a kinetic isotope effect with PET to characterize the molecular mechanism for the binding of the monoamine oxidase B (MAO B) tracer, [11C]L-deprenyl in brain; the use of PET in drug research and development and application to new CNS drugs; a critical study of the chemical purity of 2-deoxy-2- [18F]fluoro-D-glucose (FDG) introducing highly sensitive analytical methods; the optimization of targetry for producing iodine-123 and iodine- 124 from a medium energy cyclotron and; the application of robotics in quantitative PET studies. Major scientific thrusts in this renewal application will build on these advances and undertake new research including: (1) cyclotron targetry including the development of a cryogenic C18O2 target for fluorine-18 production in response to the current shortage of O-18 enriched water and the optimization of iodine-124 production for planning radiotherapy; (2) synthetic chemistry (for C-11, F-18 and 1-124) including the synthesis of NCA F-18 perchloryl fluoride ([18F]CIO3) for electrophilic fluorination; new C-1 alkylation methods; a diphenyleneiodonium conjugate for increased radioiodine stability in vivo and; the investigation of supercritical fluid chromatography as a new approach to radiotracer purification (3) radiotracer biology and mechanisms including a study of the NCA F-18 labeled catecholamines with a view to their use in neurocardiology and of [11C]RO 19 6327 a new reversible MAO B inhibitor drug an potential second generation MAO B tracer. This research builds on the strengths and diversity of the Brookhaven group and its history of major contributions in the PET field. Accomplishments in the past funding period have demonstrated this multifaceted approach to be both productive and synergistic supporting the hypothesis that a firm foundation in radiotracer chemistry and biology can lead to important advances in PET and nuclear medicine.
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