Synthesis and Evaluation of Benzylic ¹⁸F-Labeled <i>N</i>-Biphenylalkynyl Nipecotic Acid Derivatives for PET Imaging of GABA Transporter 1

As the main inhibitory neurotransmission system, the GABAergic system poses an interesting yet underutilized target for molecular brain imaging. While PET imaging of postsynaptic GABAergic neurons has been accomplished using radiolabeled benzodiazepines targeting the GABA_A receptor, the development of presynaptic radioligands targeting GABA transporter 1 (GAT1) has been unsuccessful thus far. Therefore, we developed a novel GAT1-addressing radioligand and investigated its applicability as a PET tracer in rodents. We selected a lipophilic nipecotic acid scaffold that is known to bind selectively to GAT1 as the basis for our radioligand. To obtain the desired candidate radiotracer <b>[</b>^<b>18</b><b>F]4</b>, ester-protected radioligands <b>[</b>^<b>18</b><b>F]11a-b</b> were synthesized through aliphatic nucleophilic radiofluorination of the respective bromo-precursors, after which chemical deprotection was attempted using various conditions. Because these deprotections were unsuccessful, it was evaluated whether the ethyl ester <b>[</b>^<b>18</b><b>F]11a</b> could function as a prodrug and afford the active radioligand <b>[</b>^<b>18</b><b>F]4</b> after <i>in vivo</i> ester hydrolysis by esterases. Unfortunately, PET imaging studies in a rat model using <b>[</b>^<b>18</b><b>F]11a</b> showed no brain uptake of the radiotracer. Instead, significant uptake of radioactivity was observed in the liver and bones, the latter being caused by radiodefluorination of the PET tracer. Since the PET tracer developed in this study was found to be unstable, further efforts should investigate the development of a more stable GAT1-addressing PET tracer without the potential labile benzyl fluoride moiety. Moreover, as the still intact fraction of the radiotracer did not cross the BBB, options other than the prodrug approach should be considered to increase the BBB permeability of future GAT1 radioligands.