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In Vitro Evaluation of 11 C‐Labeled ( S )‐Nicotine, ( S )‐3‐Methyl‐5‐(1‐Methyl‐2‐Pyrrolidinyl)isoxazole, and ( R,S )‐1‐Methyl‐2‐(3‐Pyridyl)azetidine as Nicotinic Receptor Ligands for Positron Emission Tomography Studies
Author(s) -
Sihver Wiebke,
Fasth KarlJohan,
Ögren Mattias,
Bivehed Håkan,
Bergström Mats,
Nordberg Agneta,
Watanabe Yasuyoshi,
Långström Bengt
Publication year - 1998
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1998.71041750.x
Subject(s) - cytisine , nicotine , stereochemistry , chemistry , epibatidine , nicotinic agonist , nicotinic acetylcholine receptor , acetylcholine receptor , in vivo , in vitro , receptor , binding site , dissociation constant , biochemistry , biology , microbiology and biotechnology , neuroscience
The binding characteristics of the novel 11 C‐labeled nicotinic ligands ( R,S )‐1‐methyl‐2‐(3‐pyridyl) azetidine (MPA) and ( S )‐3‐methyl‐5‐(1‐methyl‐2‐pyrrolidinyl)isoxazole (ABT‐418) were investigated in comparison with those of ( S )‐[ 11 C]nicotine in vitro in the rat brain to be able to predict the binding properties of the new ligands for positron emission tomography studies in vivo. The data from time‐resolved experiments for all ligands indicated fast binding kinetics, with the exception of a slower dissociation of [ 11 C]MPA in comparison with ( S )‐[ 11 C]nicotine and [ 11 C]ABT‐418. Saturation experiments revealed for all ligands two nicotinic receptor binding sites with affinity constants ( K D values) of 2.4 and 560 n M and binding site densities ( B max values) of 65.5 and 223 fmol/mg of protein for ( S )‐[ 11 C]nicotine, K D values of 0.011 and 2.2 n M and B max values of 4.4 and 70.7 fmol/mg of protein for [ 11 C]MPA, and K D values of 1.3 and 33.4 n M and B max values of 8.8 and 69.2 fmol/mg of protein for [ 11 C]ABT‐418. In competing with the 11 C‐ligands, epibatidine was most potent, followed by cytisine. A different rank order of potencies was found for (−)‐nicotine, (+)‐nicotine, MPA, and ABT‐418 displacing each of the 11 C‐ligands. Autoradiograms displayed a similar pattern of receptor binding for all ligands, whereby [ 11 C]MPA showed the most distinct binding pattern and the lowest nonspecific binding. We conclude that the three 11 C‐labeled nicotinic ligands were suitable for characterizing nicotinic receptors in vitro. The very high affinity of [ 11 C]MPA to nicotinic acetylcholine receptors, its low nonspecific binding, and especially the slower dissociation kinetics of the [ 11 C]MPA from the putative high‐affinity nicotinic acetylcholine receptor binding site compared with ( S )‐[ 11 C]nicotine and [ 11 C]ABT‐418 raise the level of interest in [ 11 C]MPA for application in positron emission tomography.