PT  - JOURNAL ARTICLE
AU  - Sowa, Alexandra
AU  - Brooks, Allen
AU  - Scott, Peter
AU  - Kilbourn, Michael
TI  - Synthesis of 1-(2-{2-[4-Fluoro-2-(4-[18F]fluorobenzoyl)phenyl]vinyloxy}ethyl)nipecotic Acid for PET imaging of GAT-1
DP  - 2016 May 01
TA  - Journal of Nuclear Medicine
PG  - 1047--1047
VI  - 57
IP  - supplement 2
4099  - http://jnm.snmjournals.org/content/57/supplement_2/1047.short
4100  - http://jnm.snmjournals.org/content/57/supplement_2/1047.full
SO  - J Nucl Med2016 May 01; 57
AB  - 1047Objectives 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.