Synthesis and positron emission tomography studies of C-11-labeled isotopomers and metabolites of GTS-21, a partial alpha7 nicotinic cholinergic agonist drug.
BACKGROUND
(3E)-3-[(2,4-dimethoxyphenyl)methylene]-3,4,5,6-tetrahydro-2,3'-bipyridine (GTS-21), a partial alpha7 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-(11)C]GTS-21 and [4-(11)C]GTS-21) along with two corresponding demethylated metabolites ([2-methoxy-(11)C]4-OH-GTS-21 and [4-methoxy-(11)C]2-OH-GTS-21) for pharmacokinetic studies in baboons and mice with positron emission tomography (PET).


RESULTS
Both [2-(11)C]GTS-21 and [4-methoxy-(11)C]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-(11)C]GTS-21 continued to clear while [4-methoxy-(11)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-(11)C]2-OH-GTS-21 (the labeled metabolite of [4-methoxy-(11)C]GTS-21) relative to [2-methoxy-(11)C]4-OH-GTS-21 (the labeled metabolite of [2-methoxy-(11)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. 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-(11)C]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.
Kim
Sung Won
SW
Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA. swkim@bnl.gov
Ding
Yu-Shin
YS
Alexoff
David
D
Patel
Vinal
V
Logan
Jean
J
Lin
Kuo-Shyan
KS
Shea
Colleen
C
Muench
Lisa
L
Xu
Youwen
Y
Carter
Pauline
P
King
Payton
P
Constanzo
Jasmine R
JR
Ciaccio
James A
JA
Fowler
Joanna S
JS
D000818:Animals; D001597:Benzylidene Compounds / Q000737:chemistry / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D007553:Isotope Labeling / Q000379:methods; D008657:Metabolic Clearance Rate; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000493:pharmacokinetics; D009928:Organ Specificity; D048530:Papio anubis; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011978:Receptors, Nicotinic / Q000187:drug effects*; D014018:Tissue Distribution; D064569:alpha7 Nicotinic Acetylcholine Receptor
D001597:Benzylidene Compounds; D002250:Carbon Radioisotopes; C579166:Chrna7 protein, mouse; D018722:Nicotinic Agonists; D011725:Pyridines; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C088936:3-(2,4-dimethoxybenzylidene)anabaseine