Development of Pyridothiophene Compounds for PET Imaging of α-Synuclein.

Aggregated α-synuclein (α-syn) protein is a pathological hallmark of Parkinson's disease (PD) and Lewy body dementia (LBD). Development of positron emission tomography (PET) radiotracers to image α-syn aggregates has been a longstanding goal.  We the pyridothiophene scaffold for α-syn PET radiotracers, where 47 derivatives of a potent pyridothiophene (asyn-44; Kd = 1.85 nM) were synthesized and screened against [3H]asyn-44 in competitive binding assays using post-mortem PD brain homogenates. Equilibrium inhibition constant (Ki) values of the most potent compounds were determined, of which three had Ki's between 12-15 nM. An autoradiography study confirmed that [3H]asyn-44 is promising for imaging  multiple system atrophy and PD. Fluorine-18 labelled asyn-44 was synthesized in 6±2% radiochemical yield (decay-corrected, n=5) with a molar activity of 263±121 GBq/µmol. Preliminary PET imaging of [18F]asyn-44 in rats showed high initial brain uptake (>1.5 standardized uptake value (SUV)), moderate washout (~0.4 SUV at 60 min), and low variability. Radiometabolite analysis showed 60-80% parent tracer in the brain after 30 and 60 mins. While [18F]asyn-44 displayed good in vitro properties and acceptable brain uptake, troublesome radiometabolites precluded further PET imaging studies. The development of additional pyridothiophene derivatives are underway, with the goal of attaining improved affinity and metabolic stability.

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