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

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, [18F]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, [68Ga]37, maintaining moderate affinity (IC50 = 134.3 nM) while
increasing hydrophilicity. Compound [68Ga]37 successfully labeled AL deposits on myocardial slices and demonstrated
rapid clearance from healthy myocardium. Overall, [68Ga]37 represents a promising PET tracer for CA imaging and warrants
further clinical evaluation.