Current status of the development of PET radiotracers for imaging alpha synuclein aggregates in Lewy bodies and Lewy neurites

Abstract

Purpose: This review provides an account of the current status of the development of PET radiotracers for imaging aggregated alpha synuclein (α-syn) in Lewy bodies and Lewy neurites. This includes a description of the various strategies used in the development of an α-syn PET probe and the technological hurdles which have limited progress in this area of research. Methods: A survey of the literature describing small molecule-based probes that bind to α-syn and have served as lead compounds for PET radiotracer development was conducted. This literature review includes a description of various radiolabeled probes having a modest affinity for α-syn which have been published within the past 5 years. Results: Although different chemical entities have been described as having a moderate affinity for α-syn, their in vitro binding affinities for α-syn and selectivities for α-syn versus beta amyloid (Aβ) and tau fibrils are not ideal for serving as lead compounds for PET radiotracer development. Structure–activity relationship (SAR) studies have generated radiolabeled probes capable of binding to α-syn, but selectivity versus Aβ and tau remains a problem. Conclusions: The development of an optimal PET probe for imaging aggregated α-syn in Lewy bodies and Lewy neurites remains as a high priority in the field pf PET radiotracer development, since it would improve the diagnosis of PD and provide a biomarker for disease progression. An α-syn PET radiotracer would also be useful in the evaluation of the efficacy of therapeutic strategies aimed at reducing levels of α-syn in the CNS. Although much progress has been made in recent years, the development of a PET radiotracer for imaging α-syn aggregates represents an unmet need in field of translational PET imaging.