Synthesis of 1-(2-{2-[4-Fluoro-2-(4-[18F]fluorobenzoyl)phenyl]vinyloxy}ethyl)nipecotic Acid for PET imaging of GAT-1

Objectives Availability of a positron emission tomography (PET) radioligand for the GABA transporter type 1 ( GAT-1) may facilitate the pre-synaptic imaging of GABA-ergic neurons. Changes in GABA-ergic neurotransmission are associated with a number of neurological (e.g. epilepsy) and psychiatric (e.g. schizophrenia, depression, Autism Spectrum Disorder, and anxiety) conditions. The objective of this work was to synthesize a GAT-1 selective PET radioligand based on a series of fluorinated unsymmetrical benzophenone-substituted nipecotic acid derivatives that have been recently described in the literature (Quandt G, et al. (2013) Bioorg Med Chem, 21, 3363).

Methods The initial target molecule chosen for radiolabeling was 1-(2-{2-[4-fluoro-2-(4-fluorobenzoyl)phenyl]-vinyloxy}ethyl)nipecotic acid, which had demonstrated in vitro inhibition of GABA uptake similar to tiagabine (FDA approved high-affinity GAT-1 inhibitor) (Quandt G, et al., 2013). As precursor the ethyl ester of the chloro-substituted analog (1-(2-{2-[4-fluoro-2-(4-chloro-benzoyl)phenyl]vinyloxy}ethyl)nipecotic acid) was prepared. That precursor was then treated with [18F]KF/K2.2.2 in DMF at 130 °C for 30 minutes, and the intermediate fluorine-18 labeled ester hydrolyzed to the acid with sodium hydroxide.

Results The [18F]fluorination was performed in a TRACERlab FXFN synthesis system. 1-(2-{2-[4-Fluoro-2-(4-[18F]fluorobenzoyl)phenyl]vinyloxy}ethyl)nipecotic acid was prepared in 13% radiochemical conversion from the chloro precursor.

Conclusions This work demonstrates the successful synthesis of a novel nipecotic acid derivative as a potential PET radioligand for the GABA transporter GAT-1. This radioligand and related nipecotic acid derivatives may facilitate in vitro and in vivo studies to better understand the changes to GABA-ergic neurotransmission in diseases and support the development of new treatments and therapeutics. Acknowledgements: Research was supported by NIH grant R21NS086758.

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