title: Regional brain uptake of the muscarinic ligand, [18F]FP-TZTP, is greatly decreased in M2 receptor knockout mice but not in M1, M3 and M4 receptor knockout mice.
abstract: A muscarinic receptor radioligand, 3-(3-(3-fluoropropyl)thio) -1,2,5,thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine (fP-TZTP) radiolabeled with the positron emitting radionuclide (18)F ([(18)F]FP-TZTP) displayed regional brain distribution consistent with M2 receptor densities in rat brain. The purpose of the present study is to further elucidate the subtype selectivity of [(18)F]FP-TZTP using genetically engineered mice which lacked functional M1, M2, M3, or M4 muscarinic receptors. Using ex vivo autoradiography, the regional brain localization of [(18)F]FP-TZTP in M2 knockout (M2 KO) was significantly decreased (51.3 to 61.4%; P<0.01) when compared to the wild-type (WT) mice in amygdala, brain stem, caudate putamen, cerebellum, cortex, hippocampus, hypothalamus, superior colliculus, and thalamus. In similar studies with M1KO, M3KO and M4KO compared to their WT mice, [(18)F]FP-TZTP uptakes in the same brain regions were not significantly decreased at P<0.01. However, in amygdala and hippocampus small decreases of 19.5% and 22.7%, respectively, were observed for M1KO vs WT mice at P<0.05. Given the fact that large decreases in [(18)F]FP-TZTP brain uptakes were seen only in M2 KO vs. WT mice, we conclude that [(18)F]FP-TZTP preferentially labels M2 receptors in vivo.
authors.affiliation: PET Department, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Jagoda
authors.forename: D O
authors.initials: DO
authors.lastname: Kiesewetter
authors.forename: K
authors.initials: K
authors.lastname: Shimoji
authors.forename: L
authors.initials: L
authors.lastname: Ravasi
authors.forename: M
authors.initials: M
authors.lastname: Yamada
authors.forename: J
authors.initials: J
authors.lastname: Gomeza
authors.forename: J
authors.initials: J
authors.lastname: Wess
authors.forename: W C
authors.initials: WC
authors.lastname: Eckelman
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D005260:Female; D005462:Fluorine Radioisotopes / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011725:Pyridines / Q000378:metabolism*; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D043588:Receptor, Muscarinic M4; D011976:Receptors, Muscarinic / Q000172:deficiency* / Q000235:genetics; D013844:Thiazoles / Q000378:metabolism*
chemical_list: D005462:Fluorine Radioisotopes; D008024:Ligands; D011725:Pyridines; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D043588:Receptor, Muscarinic M4; D011976:Receptors, Muscarinic; D013844:Thiazoles; C115177:FP-TZTP