Fluorine-18-Labeled Positron Emission Tomography Probe Targeting Activated p38α: Design, Synthesis, and In Vivo Evaluation in Rodents.

The kinase p38α, a member of the mitogen-activated protein kinase (MAPK) family, is activated by external stimuli and plays a crucial role in inflammation, tumor growth, and metabolic disorders. In particular, p38α is involved in thermogenesis and the metabolism of glucose in brown adipose tissue (BAT), and it contributes to the suppression of obesity and diabetes. The noninvasive imaging of activated p38α could help elucidate diverse pathological processes, including metabolic and inflammatory conditions. This study aimed to develop and evaluate a novel fluorine-18-labeled positron emission tomography (PET) probe for imaging activated p38α in vivo. We designed 6-(4-[F]fluoro-2-fluorophenoxy)-8-methyl-2-(tetrahydro-2-pyran-4-ylamino)-pyrido[2,3-]pyrimidin-7(8)-one ([F]R1487) by replacing a fluorine atom in R1487, which is a highly selective p38α inhibitor, with F. A tributylstannyl precursor was reacted with [F]KF in the presence of a copper catalyst to synthesize [F]R1487. Biodistribution studies and PET/computed tomography (CT) were performed on normal mice to evaluate the in vivo potential of [F]R1487. [F]R1487 was obtained with a decay-corrected radiochemical conversion of 30.6 ± 5.6% and a decay-corrected radiochemical yield of 6.9 ± 3.6% with a radiochemical purity of >99% after reversed-phase high-performance liquid chromatography purification. The biodistribution study demonstrated high and rapid radioactivity accumulation in BAT (16.3 ± 2.7 %ID/g at 5 min post-injection), with a consistently high BAT-to-blood ratio (>5 over 2 h post-injection). PET/CT imaging successfully visualized BAT with high contrast. These results suggest that [F]R1487 is a promising PET probe for imaging activated p38α in vivo, which has potential applications for pathophysiological conditions such as inflammation, cancer, and metabolic disorders.