Rational Design of Pyridinium Styryl Derivatives as PET Tracers for Cardiac Amyloidosis Imaging

作者：Qian Wang, Jianeng Song, Xiaojun Zhang, Qi‐Lei Zhang, Yuying Li, Xiao‐Xin Yan, Jiapei Dai, Jinming Zhang, Mengchao Cui · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c01485 · 被引用次数：3 · 研究领域：Amyloidosis: Diagnosis, Treatment, Outcomes、Peptidase Inhibition and Analysis、Trace Elements in Health

Cardiac amyloidosis (CA) is a complex restrictive cardiomyopathy, and while treatment options are advancing rapidly, specific diagnostic probes for CA have rarely been developed or reported. In this study, a series of pyridinium styryl derivatives were designed and synthesized, exhibiting specific affinity for immunoglobulin light chain protein amyloidosis (AL). Through a structure–activity relationship analysis and bioevaluations, [ 18 F] 23 was identified as the first candidate for PET/CT imaging in rodents. However, due to its increasing lipophilicity, the uptake in healthy myocardium remained high (SUV = 3.8) during imaging, making it unsuitable for detecting myocardial amyloidosis. Subsequently, we rationally designed and optimized the second candidate, [ 68 Ga] 37, maintaining moderate affinity (IC 50 = 134.3 nM) while increasing hydrophilicity. Compound [ 68 Ga] 37 successfully labeled AL deposits on myocardial slices and demonstrated rapid clearance from healthy myocardium. Overall, [ 68 Ga] 37 represents a promising PET tracer for CA imaging and warrants further clinical evaluation.