title: Synthesis and positron emission tomography studies of C-11-labeled isotopomers and metabolites of GTS-21, a partial alpha7 nicotinic cholinergic agonist drug.
abstract: 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.
authors.affiliation: Medical Department, Brookhaven National Laboratory, Upton, NY 11973, USA. swkim@bnl.gov
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Kim
authors.forename: Yu-Shin
authors.initials: YS
authors.lastname: Ding
authors.forename: David
authors.initials: D
authors.lastname: Alexoff
authors.forename: Vinal
authors.initials: V
authors.lastname: Patel
authors.forename: Jean
authors.initials: J
authors.lastname: Logan
authors.forename: Kuo-Shyan
authors.initials: KS
authors.lastname: Lin
authors.forename: Colleen
authors.initials: C
authors.lastname: Shea
authors.forename: Lisa
authors.initials: L
authors.lastname: Muench
authors.forename: Youwen
authors.initials: Y
authors.lastname: Xu
authors.forename: Pauline
authors.initials: P
authors.lastname: Carter
authors.forename: Payton
authors.initials: P
authors.lastname: King
authors.forename: Jasmine R
authors.initials: JR
authors.lastname: Constanzo
authors.forename: James A
authors.initials: JA
authors.lastname: Ciaccio
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Fowler
mesh_terms: 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
chemical_list: 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