An era of precision: Emerging, research, and adjunct radiotracers for nuclear imaging of cardiac amyloidosis.

Cardiac amyloidosis (CA) has rapidly transitioned from an underrecognized cause of heart failure to a treatable protein-misfolding cardiomyopathy, driven by advances in transthyretin (TTR) stabilization and gene silencing, and immunotherapy to control monoclonal light chain production. Noninvasive diagnosis of transthyretin cardiac amyloidosis (ATTR) using technetium-99m bone-avid scintigraphy is now routine, yet these tracers do not bind amyloid and offer limited amyloid specificity, quantification, or monitoring of response to therapy. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) agents that directly engage amyloid or key downstream processes (fibroblast activation, inflammation, denervation) may redefine the diagnostic algorithm, phenotyping, risk stratification, and longitudinal assessment. Among these, iodine [124I]evuzamitide (AT-01), a radioiodinated, pan-amyloid-binding peptide targeting amyloid fibrils and amyloid associated heparan sulfate proteoglycans, has emerged as the first amyloid-specific PET radiotracer to receive U.S. FDA Breakthrough Therapy designation for CA and has completed a Phase 3 pivotal evaluation. [18F]Florbetaben is similarly poised in a pivotal Phase 3 study. Herein, we summarize 1) Emerging radiotracers primed for clinical availability, including the pan-amyloid peptide tracers, [124I]evuzamitide and [99mTc]p5+14, the stilbene-based small molecule [18F]florbetaben, and the protein-based radiotracer, [99mTc]aprotinin; 2) Research-focused, Aβ amyloid radiotracers and their performance in CA ([11C]PiB; [18F]florbetapir, [18F]flutemetamol; and newer [18F]florbetazine); and 3) Adjunct radiotracers for exploring myocardial microenvironment ([68Ga]FAPI, and others), emphasizing rationale for use, opportunities, synergies, strengths, limitations, and regulatory status. Finally, we outline future research and molecular targets to elucidate the pathology and the impact of novel amyloid therapeutics as they become available.