Protonation-Guided Design and Evaluation of Selective PET Tracers for Light Chain Cardiac Amyloidosis

Early detection of cardiac amyloidosis (CA) is challenging, despite advances in repurposed β -amyloid PET tracers and amyloid-targeted [ ¹²⁴ I]Evuzamitide. The heterogeneity of CA subtypes requires invasive tests, like tissue biopsy, before targeted therapy can begin. Amyloidogenic light chains (AL) expose negatively charged pockets enriched in acidic residues and N-glycosylated modifications, guiding the design of selective molecular probes. We showed that protonation-driven recognition accomplishes unprecedented selectivity for AL deposits. Using this principle, we developed a fluorinated derivative, [ ¹⁸ F] FT-8 , based on a 4-pyridylpiperazine scaffold, which displayed high binding affinity ( K _i = 11.52 nM) and selectivity towards AL, as well as favorable pharmacokinetics. In first-in-human PET studies, [ ¹⁸ F] FT-8 provided high-contrast visualization of AL deposits in the myocardium and extracardiac organs with significant specificity. These findings position [ ¹⁸ F] FT-8 as a promising PET tracer for advancing the non-invasive differential diagnosis of AL-CA and highlighting the role of protonation in developing new-generation molecular probes across diverse disease contexts.