Abstract
388
Objectives: (E)-3-(2,4-dimethoxybenzylidene)anabaseine (GTS-21), an α7 nicotinic acetylcholine receptor agonist, is being evaluated in humans for treatment of schizophrenia and Alzheimer's disease. One of its major demethylated metabolites, 4-OH-GTS-21 was suggested to contribute to its therapeutic effects. To better understand the role of GTS-21 and its metabolites in the brain, we labeled GTS-21 and its metabolites with C-11 for pharmacokinetic studies in baboons and rodents. Methods: Two isotopomers of GTS-21 ([2-methoxy-11C] and [4-methoxy-11C]GTS-21) and two labeled metabolites (2-OH- and 4-OH-[methoxy-11C]GTS-21) were synthesized from [11C]CH3I and their respective nor-precursors. Their pharmacokinetics in baboon brain were compared using PET. MicroPET studies of the two isotopomers were performed in mice followed by ex vivo analysis. Results: Radiochemical yields were 20-43% for both isotopomers and 12-16% for labeled metabolites. Specific activities ranged from 0.8 to 6 Ci/μmol. Both isotopomers showed rapid global brain uptake and clearance. The distribution volumes were identical until 27 min, after which C-11 uptake was higher for [4-methoxy-11C]GTS-21 than [2-methoxy-11C]GTS-21. The C-11 brain uptake of 2-OH-[methoxy-11C]GTS-21 was 4 times greater than 4-OH-[methoxy-11C]GTS-21 and 2 times lower than [11C]GTS-21 at 2.5 min post IV injection. The major chemical form in the mouse brain was GTS-21. Conclusions: Although initial brain uptake of [11C]GTS-21 was high and widespread, clearance was rapid resulting in low brain retention by 30 min. The higher blood-brain barrier penetration of 2-OH-[methoxy-11C]GTS-21 suggests that 2-OH-GTS-21 could partake in the therapeutic effects and could also contribute to the difference in pharmacokinetics between two isotopomers. In addition, [2-methoxy-11C]GTS-21 better reflects GTS-21 in the brain whereas with [4-methoxy-11C]GTS-21, the image reflects both parent drug and labeled metabolite. This study illustrates the value of comparing different label positions and labeled metabolites to gain insight on the behavior of CNS drug and their metabolites in the brain providing an important perspective on drug pharmacokinetics.
Research Support (if any): DOE-OBER and NIDA K05 DA 020001
- Society of Nuclear Medicine, Inc.