Organocatalytic Asymmetric Synthesis of SynVesT-1, a Synaptic Density Positron Emission Tomography Imaging Agent

Abstract

Heterocyclic nonacetamide ligands are used as positron emission tomography (PET) imaging agents of the synaptic vesicle glycoprotein 2A (SV2A), with potential applications in the diagnosis of various neuropsychiatric diseases. To date, the main synthetic strategy to access these optically active compounds has involved the racemic synthesis of a late-stage intermediate followed by the separation of the enantiomers. Here, we describe the use of iminium organocatalysis for the asymmetric synthesis of SynVesT-1, an important PET imaging agent of SV2A. The key step involved the conjugate addition of nitromethane with a cinnamaldehyde in the presence of the Jørgensen−Hayashi catalyst using the Merck dual acid cocatalyst system. Pinnick-type oxidation and esterification of the adduct was then followed by chemoselective nitro group reduction and cyclization using nickel borate. N-Alkylation of the resulting lactam then completed the seven-step synthesis of SynVesT-1. This approach was amenable for the synthesis of an organotin analogue, which following copper(II)-mediated fluoro-destannylation allowed rapid access to [ 18 F]SynVesT-1.

Association of synaptic density and cognitive performance in temporal lobe epilepsy: Humans and animals PET imaging study with [18F]SynVesT‐1

“…16,17 [ 18 F]SynVesT-1 is a PET tracer recently developed for SV2A and has been used in human studies. [18][19][20] Previous research has shown reductions of SV2A binding in the hippocampal region of patients with TLE compared to healthy controls. 21 These studies emphasized regional SV2A uptake changes or quantified predefined abnormal regions in PET images, but without comprehensively considering the role of cognitive co-morbidities in synaptic loss.…”

“…SV2A, expressed in almost all synapses and located within the synaptic vesicles at presynaptic terminals, 15 serves as the binding site for the antiseizure medication (ASM) levetiracetam (LEV) 16,17 . [ 18 F]SynVesT‐1 is a PET tracer recently developed for SV2A and has been used in human studies 18–20 . Previous research has shown reductions of SV2A binding in the hippocampal region of patients with TLE compared to healthy controls 21 .…”