Stony Brook University

Introduction: GTS-21 ((3E)-3-[(2,4-dimethoxyphenyl)methylene]-3,4,5,6tetrahydro-2,3’-bipyridine), a partial α7 nicotinic acetylcholine receptor agonist drug, has recently been shown to improve cognition in schizophrenia and Alzheimer’s disease. One of its two major demethylated metabolites, 4-OH-GTS-21, has been suggested to contribute to its therapeutic effects. Methods: We labeled GTS-21 in two different positions with carbon-11 ([2methoxy-C]GTS-21 and [4-methoxy-C]GTS-21) along with two corresponding demethylated metabolites ([2-methoxy-C]4-OH-GTS-21 and [4-methoxy-C]2-OHGTS-21) for pharmacokinetic studies in baboons and mice with PET. Results: Both [2-methoxy-C]GTS-21 and [4-methoxy-C]GTS-21 showed similar initial high rapid uptake in baboon brain, peaking from 1-3.5 min (0.0270.038 %ID/cc) followed by rapid clearance (t1/2 <15 min), resulting in low brain retention by 30 min. However, after 30 min, [2-methoxy-C]GTS-21 continued to clear while [4methoxy-C]GTS-21 plateaued, suggesting the entry of a labeled metabolite into the brain. Comparison of the pharmacokinetics of the two labeled metabolites confirmed expected higher brain uptake and retention of [4-methoxy-C]2-OH-GTS-21 (the labeled metabolite of [4-methoxy-C]GTS-21) relative to [2-methoxy-C]4-OH-GTS-21 (the labeled metabolite of [2-methoxy-C]GTS-21) which had negligible brain uptake. Ex vivo studies in mice showed that GTS-21 is the major chemical form in the mouse brain.