Development of Positron Emission Tomography Radiotracers for the GABA Transporter 1.
In vivo positron emission tomography (PET) imaging of the γ-aminobutyric acid (GABA) receptor complex has been accomplished using radiolabeled benzodiazepine derivatives, but development of specific presynaptic radioligands targeting the neuronal membrane GABA transporter type 1 (GAT-1) has been less successful. The availability of new structure-activity studies of GAT-1 inhibitors and the introduction of a GAT-1 inhibitor (tiagabine, Gabatril) into clinical use prompted us to reinvestigate the syntheses of PET ligands for this transporter. Initial synthesis and rodent PET studies of N-[11C]methylnipecotic acid confirmed the low brain uptake of that small and polar molecule. The common design approach to improve blood-brain barrier permeability of GAT-1 inhibitors is the attachment of a large lipophilic substituent. We selected an unsymmetrical bis-aromatic residue attached to the ring nitrogen by a vinyl ether spacer from a series recently reported by Wanner and coworkers. Nucleophilic aromatic substitution of an aryl chloride precursor with [18F]fluoride was used to prepare the desired candidate radiotracer ( R, E/ Z)-1-(2-((4-fluoro-2-(4-[18F]fluorobenzoyl)styryl)oxy)ethyl)piperidine-3-carboxylic acid (( R, E/ Z)-[18F]10). PET studies in rats showed no brain uptake, which was not altered by pretreatment of animals with the P-glycoprotein inhibitor cyclosporine A, indicating efflux by Pgp was not responsible. Subsequent PET imaging studies of ( R, E/ Z)-[18F]10 in rhesus monkey brain showed very low brain uptake. Finally, to test if the free carboxylic acid group was the likely cause of poor brain uptake, PET studies were done using the ethyl ester derivative of ( R, E/ Z)-[18F]10. Rapid and significant monkey brain uptake of the ester was observed, followed by a slow washout over 90 min. The blood-brain barrier permeability of the ester supports a hypothesis that the free acid function limits brain uptake of nipecotic acid-based GAT-1 radioligands, and future radiotracer efforts should investigate the use of carboxylic acid bioisosteres.
['Sowa|Alexandra R|AR|', 'Brooks|Allen F|AF|0000-0003-3773-3024', 'Shao|Xia|X|', 'Henderson|Bradford D|BD|', 'Sherman|Philip|P|', 'Arteaga|Janna|J|', 'Stauff|Jenelle|J|', 'Lee|Adam C|AC|', 'Koeppe|Robert A|RA|', 'Scott|Peter J H|PJH|0000-0002-6505-0450', 'Kilbourn|Michael R|MR|']
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 D000818:Animals D001812:Blood-Brain Barrier D001921:Brain D016572:Cyclosporine D004791:Enzyme Inhibitors D004952:Esters D005462:Fluorine Radioisotopes D050485:GABA Plasma Membrane Transport Proteins D058805:GABA Uptake Inhibitors D008253:Macaca mulatta D010539:Permeability D010880:Piperidines D049268:Positron-Emission Tomography D019275:Radiopharmaceuticals D051381:Rats D013237:Stereoisomerism D000078308:Tiagabine
positron emission tomography GABA transporter fluorine-18