Synthesis and positron emission tomography studies of C-11-labeled isotopomers and metabolites of GTS-21, a partial α7 nicotinic cholinergic agonist drug

Kim, Sung Won; Ding, Yu-Shin; Alexoff, David; Patel, Vinal; Logan, Jean; Lin, Kuo-Shyan; Shea, Colleen; Muench, Lisa; Xu, Youwen; Carter, Pauline; King, Payton; Constanzo, Jasmine R.; Ciaccio, James A.; Fowler, Joanna S.

doi:10.1016/j.nucmedbio.2007.04.005

« Previous Next »Nuclear Medicine and Biology
Volume 34, Issue 5 , Pages 541-551, July 2007

Synthesis and positron emission tomography studies of C-11-labeled isotopomers and metabolites of GTS-21, a partial α7 nicotinic cholinergic agonist drug

Sung Won Kim
- Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA
- Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, USA
- Corresponding author. Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, USA. Tel.: +1 631 344 4393; fax: +1 631 344 5815.
Yu-Shin Ding
- Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, USA
- Department of Radiology, Yale University School of Medicine, New Haven, CT 06520-8048, USA
David Alexoff
- Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA
Vinal Patel
- Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA
Jean Logan
- Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA
Kuo-Shyan Lin
- Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, USA
Colleen Shea
- Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA
Lisa Muench
- Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA
Youwen Xu
- Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA
Pauline Carter
- Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA
Payton King
- Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA
Jasmine R. Constanzo
- Department of Chemistry, Fordham University, Bronx, NY 10458, USA
James A. Ciaccio
- Department of Chemistry, Fordham University, Bronx, NY 10458, USA
Joanna S. Fowler
- Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA
- Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, USA
- Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA

Received 12 February 2007; received in revised form 2 April 2007; accepted 10 April 2007.

Abstract

Introduction

(3E)-3-[(2,4-dimethoxyphenyl)methylene]-3,4,5,6-tetrahydro-2,3′-bipyridine (GTS-21), 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 ([2-methoxy-¹¹C]GTS-21 and [4-¹¹C]GTS-21) along with two corresponding demethylated metabolites ([2-methoxy-¹¹C]4-OH-GTS-21 and [4-methoxy-¹¹C]2-OH-GTS-21) for pharmacokinetic studies in baboons and mice with positron emission tomography (PET).

Results

Both [2-¹¹C]GTS-21 and [4-methoxy-¹¹C]GTS-21 showed similar initial high rapid uptake in baboon brain, peaking from 1 to 3.5 min (0.027–0.038%ID/cc) followed by rapid clearance (t_1/2<15 min), resulting in low brain retention by 30 min. However, after 30 min, [2-methoxy-¹¹C]GTS-21 continued to clear while [4-methoxy-¹¹C]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-¹¹C]2-OH-GTS-21 (the labeled metabolite of [4-methoxy-¹¹C]GTS-21) relative to [2-methoxy-¹¹C]4-OH-GTS-21 (the labeled metabolite of [2-methoxy-¹¹C]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. Whole-body dynamic PET imaging in baboon and mouse showed that the major route of excretion of C-11 is through the gallbladder.

Conclusions

The major findings are as follows: (a) extremely rapid uptake and clearance of [2-methoxy-¹¹C]GTS-21 from the brain, which may need to be considered in developing optimal dosing of GTS-21 for patients, and (b) significant brain uptake of 2-OH-GTS-21, suggesting that it might contribute to the therapeutic effects of GTS-21. This study illustrates the value of comparing different label positions and labeled metabolites to gain insight on the behavior of a central nervous system drug and its metabolites in the brain, providing an important perspective on drug pharmacokinetics.

Keywords: [¹¹C]GTS-21, Carbon-11, α7 Nicotinic acetylcholine receptor, Drug pharmacokinetics, PET, Labeled metabolites