Development of Pyridothiophene Compounds for PET Imaging of α-Synuclein.
Chemistry
; 30(23): e202303921, 2024 Apr 22.
Article
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| ID: mdl-38354298
ABSTRACT
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. This work explores the suitability of a pyridothiophene scaffold for α-syn PET radiotracers, where 47 derivatives of a potent pyridothiophene (asyn-44; Kd=1.85â
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 in the lower nanomolar range (12-15â
nM). An autoradiography study confirmed that [3H]asyn-44 is promising for imaging brain sections from multiple system atrophy and PD donors. 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 60â
min), and low variability. Radiometabolite analysis showed 60-80 % parent tracer in the brain after 30 and 60â
mins. While [18F]asyn-44 displayed good inâ
vitro properties and acceptable brain uptake, troublesome radiometabolites precluded further PET imaging studies. The synthesis and inâ
vitro evaluation of additional pyridothiophene derivatives are underway, with the goal of attaining improved affinity and metabolic stability.
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MEDLINE
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En
Revista:
Chemistry
Asunto de la revista:
QUIMICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Canadá