An ultrahigh throughput in silico screen was conducted on 42 M compounds in the Mcule database and led to the identification of a new lead compound for radiotracer development for use with the imaging technique, positron emission tomography.

The accumulation of aggregated α-synuclein (α-syn) is a pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Here within, we report the in vitro characterization targeting site 2 of α-syn fibrils and in vivo evaluation of NHPs of KAC-50.1 as a potential α-syn positron emission tomography (PET) radioligand. Preclinical studies were performed using a multidimensional approach of post-mortem brain imaging techniques, radioligand binding, and biochemical studies. These experiments were followed by PET imaging in cynomolgus monkeys using [¹¹C]KAC-50.1. [3H]KAC-50.1 displayed a KD of 35 nM toward site 2 in recombinant α-syn fibrils. Specific binding of [3H]KAC-50.1 was observed in brain tissues with abundant α-syn pathology but also in AD, PSP, and CBD cases, indicating binding to amyloid β (Aβ) and tau pathology. PET studies showed a rapid entrance of [¹¹C]KAC-50.1 into the brain and relatively rapid washout from cortical brain regions, with slower washout in subcortical regions. [3H]KAC-50.1 is a ligand that binds to fibrillar α-syn but shows limited selectivity for α-syn versus Aβ and tau fibrils. PET studies in NHPs indicate that [¹¹C]KAC-50.1, despite reversible kinetic properties, displays retention in white matter. Altogether, the in vitro and in vivo properties do not support further development of [¹¹C]KAC-50.1 as a PET imaging agent.

A novel brain positron emission tomography (PET) radioligand, [¹¹C]HY-2-15, has potential for imaging alpha-synuclein aggregations in multiple system atrophy and misfolded tau proteins in tauopathies, based on its high binding affinity in disease brain tissue homogenates. Here, we demonstrate that [³H]HY-2-15 has the capability to bind to aggregated alpha-synuclein in multiple system atrophy brain and tau aggregations in progressive supranuclear palsy and corticobasal degeneration brain tissues via in vitro autoradiography study. A first-in-human pilot multicenter clinical study recruited a total of 10 subjects including healthy controls and patients with Parkinson’s disease, multiple system atrophy, or progressive supranuclear palsy. The study revealed that [¹¹C]HY-2-15 has a relatively higher specific uptake in the pallidum and midbrain of patients with progressive supranuclear palsy. Total-body scans performed on the PennPET Explorer showed the radiotracer was cleared by renal excretion. However, the rapid metabolism and low brain uptake resulted in a limited signal of [¹¹C]HY-2-15 in brain.

Structure-activity relationship studies were performed on a library of synthesized compounds based on previously identified tau ligands. The top 13 new compounds had K_i values in the range of 5-14 nM in Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) post-mortem brain tissues. One of the more promising new compounds ([³H]75) bound with high affinity in AD, PSP, and CBD tissues (K_D's = 1-1.5 nM) and Pick's disease tissue (K_D = 3.8 nM). Autoradiography studies with [³H]75 demonstrated specific binding in AD, PSP, and CBD post-mortem tissues. Nonhuman primate brain PET imaging with [¹⁸F]75 demonstrated a peak standardized uptake value (SUV) of ∼5 in the cerebellum, ∼4.5 in the cortex, and ∼4 in whole brain with SUV 2-to-90 min ratios of 3.9 in whole brain, 4.9 in cortex, and 4.5 in cerebellum. Compound [¹⁸F]75 is a promising candidate for translation to human brain PET imaging studies.

Parkinson’s disease (PD) is a multifaceted neurodegenerative disorder characterized by dopaminergic neuronal loss and widespread α-synuclein pathology. Nuclear medicine imaging offers essential in vivo tools for early diagnosis, differential assessment, and monitoring disease progression. This review summarizes key PET and SPECT radiotracers targeting dopaminergic synthesis and transport, vesicular storage, post-synaptic receptors, neuroinflammation, and protein aggregation, highlighting their roles in clinical evaluation and phenotyping. Clinically, these modalities support earlier recognition of PD, distinction from atypical parkinsonian syndromes, and assessment of non-motor involvement. Future directions include the development of selective α-synuclein tracers and multimodal imaging strategies to refine prodromal detection and guide personalized therapeutic interventions.