Radiopharmaceuticals driving the transition from metabolic to targeted precision molecular imaging in neurodegenerative diseases

Abstract

Neurodegenerative diseases (NDDs) are characterized by overlapping clinical phenotypes and heterogeneous proteinopathies, which pose substantial challenges for early and accurate diagnosis. Molecular imaging with radiopharmaceuticals has revolutionized the field by enabling the in vivo visualization of disease-specific biological processes. Historically, the field has progressed from glucose metabolism imaging toward the increasingly selective detection of pathological protein aggregates. Amyloid-β and tau are established biomarkers in Alzheimer’s disease, and their imaging is now integrated into diagnostic and therapeutic pathways. Nevertheless, ongoing efforts continue to refine these radiopharmaceuticals, particularly in enhancing target specificity and minimizing off-target binding. In parallel, emerging targets such as α-synuclein, mutant huntingtin, transactive response DNA binding protein 43, and other pathological aggregates are expanding the molecular imaging toolbox beyond Alzheimer’s disease to encompass a broader spectrum of NDDs. Neuroinflammation-targeted PET provides an additional window into disease-associated biological processes beyond protein aggregation. Nevertheless, a critical need persists for radiopharmaceuticals targeting these emerging molecular targets. Addressing these challenges and advancing multi-target PET platforms will not only enable in vivo detection of mixed proteinopathies and precise disease subtyping, but also provide a core infrastructure for target validation, companion diagnostics, and therapeutic monitoring across the drug development pipeline, ultimately ushering in an era of biologically defined precision medicine for NDDs.