Muscarinic Receptor PET in Neurodegeneration: Promise, Pitfalls, and Translational Priorities

Positron emission tomography (PET) of muscarinic acetylcholine receptors has evolved from a receptor-mapping exercise into a potential translational tool for probing cholinergic dysfunction in neurodegenerative disease. However, the field still lacks a clear hierarchy of clinical value across receptor subtypes, tracers, and quantitative analysis strategies, including acquisition protocols and kinetic modeling approaches. In the M₂ arena, [¹⁸F]FP-TZTP has been associated with higher distribution volumes in older APOE-ε4 carriers, but the biological meaning of this signal remains uncertain in the absence of longitudinal conversion data and with quantification approaches that are difficult to implement routinely. Among M₄ ligands, [¹¹C]MK-6884 is the most advanced and reproducible tracer to date, yet its clinical evidence still rests on proof-of-concept studies, mainly in moderate-to-severe Alzheimer's disease, with important methodological limitations. In our view, muscarinic PET should now be reframed less as a stand-alone diagnostic biomarker and more as a platform for mechanistic and pharmacodynamic studies, especially for the development and monitoring of muscarinic-positive allosteric modulators. Future progress will depend on longitudinal multicenter validation, simplified quantification pipelines, and next-generation PET systems capable of capturing tracer kinetics more efficiently.