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• W2602832341 abstract "This work sought to radiolabel novel positron-emitting radiotracers and evaluate their utility for quantifying enzymes relevant to neurological and psychiatric disorders via position emission tomography (PET) in preclinical studies. Four enzymes were targeted: glycogen synthase kinase 3 (GSK-3), fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), and monoamine oxidase B (MAO-B). By adapting a [11C]CO2 fixation method, a GSK-3 inhibitor with a 1-aryl-3-benzyl-[11C-carbonyl]urea scaffold was synthesized and represents a technique for radiolabeling unsymmetrical ureas bearing aromatic substrates. Using a similar method, we were able to prepare a 11C isotopologue of PF-04457845, a new investigation agent targeting FAAH in phase 2 trials. [11C]PF-04457845 was prepared in 5% radiochemical yield (uncorrected, based on [11C]CO2) and high radiochemical purity (>98%) with a specific activity of 74 GBq/µmol. Following ex vivo biodistribution and specificity experiments in rats, it was determined that [11C]PF-04457845 was a promising candidate which should be assessed in higher species. Further expanding the [11C]CO2 fixation method, five candidate radiotracers targeting MAGL were prepared in high radiochemical purity with sufficient yield and specific activity for conducting preclinical evaluations. Although none of these sufficiently penetrated the rodent brain, they represent rare examples for attempting to image this important neurological target with PET. Furthermore, the low nucleophilicity of the alcohol and amines used to prepare the [11C]carbamate- and [11C]urea-based radiotracers broadened the scope of the [11C]CO2 fixation method. Lastly, a [18F]fluoropropyl derivative of a reversibly-binding MAO-B inhibitor, SL25.1188, was synthesized in 52% radiochemical yield (uncorrected, based on [18F]F-) with a specific activity of 109 GBq/µmol and had high radiochemical purity (>98%); however, low MAO-B affinity and rapid metabolism in rat plasma led to poor brain uptake. Our efforts to expand the basic knowledge of new 11C- and 18F-labeled compounds to non-invasively probe important neurological enzyme targets are discussed herein." @default.
• W2602832341 created "2017-04-07" @default.
• W2602832341 creator A5067114921 @default.
• W2602832341 date "2015-06-01" @default.
• W2602832341 modified "2023-09-23" @default.
• W2602832341 title "Development and Preclinical Evaulation of Novel Enzyme-targeting Radiotracers for Positron Emission Tomography" @default.
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