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 [¹⁸F]SynVesT-1.

A series of fluorinated 6-arylaminobenzamides have been shown to be selective and potent agonists of the sphingosine-1-phosphate-5 receptor. Radiofluorination and PET imaging with the lead compound showed fast uptake in rat brain and spinal cord.

Synthesis and biological testing of the R - and S -enantiomers of LW223, a third generation TSPO PET imaging agent using human brain tissue showed that despite a 7.5-fold difference in affinity, both are insensitive to rs6971 polymorphism.