Discovery and characterization of UCB-1A: the first PET radioligand for imaging synaptic vesicle glycoprotein 2C

Abstract

The synaptic vesicle glycoprotein 2C (SV2C) is a synaptic protein involved in the regulation of dopamine release. It is expressed in striatum, globus pallidus and substantia nigra, regions involved in the regulation of motor function. Genome-wide association studies, animal model and human brain tissue data indicate a strong link between SV2C and Parkinso[n]s disease, suggesting a potential role of SV2C as synaptic marker for Parkinso[n]s disease. We hypothesize that a positron emission tomography (PET) radioligand for SV2C can serve as imaging marker for Parkinso[n]s disease, enabling early diagnosis and assessment of disease progression. This study was therefore designed to develop a PET radioligand for imaging SV2C. UCB-1A was the lead candidate selected from a library of compounds developed by UCB BioPharma. A translational approach was used, including autoradiography and in vitro binding studies with [3H]UCB-1A, and in vivo PET studies with [11C]UCB-1A in non-human primates (NHPs). The KD of [3H]UCB-1A for rat and human SV2C ranged between 6 and 15 nM, with >100-fold selectivity towards SV2A and SV2B. Specific binding of [3H]UCB-1A in rat and NHP brains was observed in substantia nigra, globus pallidus, striatum and brainstem nuclei, consistent with the expression of SV2C, and was decreased in the striatum of 6-hydroxydopamine-lesioned rats and in the putamen of Parkinson donors. UCB-1A was successfully radiolabelled with 11C and PET studies in NHPs demonstrated that [11C]UCB-1A displays suitable pharmacokinetic properties, a brain distribution consistent with the expression of SV2C and is selective for SV2C. [11C]UCB-1A is the first PET radioligand for in vivo imaging of SV2C and a potential synaptic marker for in vivo studies in Parkinso[n]s disease.