Randall Lee Carter

Radiosynthesis and ex vivo evaluation of [18F]-(S)-3-(6-(3-fluoropropoxy)benzo[d]isoxazol-3-yl)-5-(methoxymethyl)oxazolidin-2-one for imaging MAO-B with PET

Carbon-11 labeled SL25.1188 ((S)-5-(methoxymethyl)-3-(6-(4,4,4-trifluorobutoxy)benzo[d]isoxazol-3-yl)oxazolidin-2-one) is a reversible radiotracer for monoamine oxidase B that was recently evaluated in healthy volunteers by positron emission tomography (PET). Herein we report the preparation and ex vivo evaluation of a fluorinated SL25.1188 derivative as a candidate (18)F-labeled PET radiotracer. (S)-3-(6-(3-fluoropropoxy)benzo[d]isoxazol-3-yl)-5-(methoxy methyl)oxazolidin-2-one (1) was labeled with fluorine-18 in 51% uncorrected radiochemical yield having high radiochemical purity (>98%) and specific activity (109±26GBq/μmol). Ex vivo biodistribution studies demonstrated low radioactivity retention, specific binding and metabolic stability within rat brains. High uptake of radioactivity in bone is consistent with metabolic defluorination. In vitro binding assays of longer chain fluoroalkoxy derivatives revealed that the length of the carbon chain is an integral feature in MAO-B inhibitor potency and selectivity within this scaffold.

Head-to-head comparison of 11C-PBR28 and 18F-GE180 for the quantification of TSPO in the human brain

18F-GE180 is a third-generation PET tracer for quantifying the translocator protein (TSPO), a biomarker for inflammation. The aim of this study was to perform a head-to-head comparison of 18F-GE180 and the well-established TSPO tracer 11C-PBR28 by scanning with both tracers during the same day in the same subjects. Methods: Five subjects underwent a 90-min PET scan with 11C-PBR28 in the morning and 18F-GE180 in the afternoon. A metabolite-corrected arterial input function was obtained in each subject for both tracers, and the brain uptake was quantified with a 2-tissue-compartment model. Results: The rate of metabolism of 18F-GE180 in arterial blood was slower than that of 11C-PBR28 (the percentages of nonmetabolized parent in plasma at 90 min were 74.9% ± 4.15% [mean ± SD] and 11.2% ± 1.90%, respectively). The plasma free fractions were similar for both tracers: 3.5% ± 1.1% for 18F-GE180 and 4.1% ± 1.1% for 11C-PBR28. The average total volume of distribution (VT) of 18F-GE180 was about 20 times smaller than that of 11C-PBR28 (0.15 ± 0.03 mL/cm3 for 18F-GE180 and 3.27 ± 0.66 mL/cm3 for 11C-PBR28). 18F-GE180 was characterized by poor transfer from the vascular compartment to the brain (its plasma-to-tissue rate constant [K1] was about 10 times smaller than that of 11C-PBR28). Moreover, kinetic modeling was more difficult with 18F-GE180, as its VT values were identified with a lower precision than those of 11C-PBR28 and outlying values were more frequent. Conclusion: The VT of 18F-GE180 was about 20 times smaller than that of 11C-PBR28 because of low penetration into the brain from the vascular compartment. In addition, kinetic modeling of 18F-GE180 was more challenging than that of 11C-PBR28. Therefore, compared with 11C-PBR28, 18F-GE180 had unfavorable characteristics for TSPO imaging of the brain.