Futatsugi Mikiya, Miyazaki Anna, Kanai Yasukazu, Kondo Naoya, Temma Takashi
Department of Biofunctional Analysis, Graduate School of Pharmaceutical Sciences, Osaka Medical and Pharmaceutical University, 4-20-1 Nasahara, Takatsuki 569-1094, Osaka, Japan.
Kansai BNCT Medical Center, Educational Foundation of Osaka Medical and Pharmaceutical University, 2-7 Daigakumachi, Takatsuki 569-8686, Osaka, Japan.
Pharmaceuticals (Basel). 2025 Apr 20;18(4):600. doi: 10.3390/ph18040600.
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.
激酶p38α是丝裂原活化蛋白激酶（MAPK）家族的成员之一，可被外部刺激激活，在炎症、肿瘤生长和代谢紊乱中起关键作用。特别是，p38α参与棕色脂肪组织（BAT）的产热和葡萄糖代谢，并有助于抑制肥胖和糖尿病。活化p38α的无创成像有助于阐明包括代谢和炎症状态在内的多种病理过程。本研究旨在开发和评估一种新型的氟-18标记正电子发射断层扫描（PET）探针，用于在体内对活化的p38α进行成像。我们通过将R1487（一种高度选择性的p38α抑制剂）中的一个氟原子替换为F，设计了6-(4-[F]氟-2-氟苯氧基)-8-甲基-2-(四氢-2-吡喃-4-基氨基)-吡啶并[2,3-]嘧啶-7(8)-酮（[F]R1487）。三丁基锡前体在铜催化剂存在下与[F]KF反应，合成[F]R1487。对正常小鼠进行生物分布研究和PET/计算机断层扫描（CT），以评估[F]R1487的体内潜力。[F]R1487经反相高效液相色谱纯化后，衰变校正后的放射化学转化率为30.6±5.6%，衰变校正后的放射化学产率为6.9±3.6%，放射化学纯度>99%。生物分布研究表明，BAT中放射性快速高积累（注射后5分钟时为16.3±2.7 %ID/g），注射后2小时内BAT与血液的比值始终较高（>5）。PET/CT成像成功地以高对比度显示了BAT。这些结果表明，[F]R1487是一种有前景的用于在体内对活化p38α进行成像 的PET探针，在炎症、癌症和代谢紊乱等病理生理状况方面具有潜在应用。
