title: Inhibition of [18F]FP-TZTP binding by loading doses of muscarinic agonists P-TZTP or FP-TZTP in vivo is not due to agonist-induced reduction in cerebral blood flow.
abstract: [(18)F][3-(3-(3-Fluoropropyl)thio)-1,2,5-thiadiazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine ([(18)F]FP-TZTP) is an M2 selective muscarinic agonist that may allow noninvasive studies of Alzheimer's disease with PET. 3-(3-(Propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine (P-TZTP), a nonfluorinated analog of FP-TZTP, and unlabeled FP-TZTP inhibited [(18)F]FP-TZTP binding in vivo. Because muscarinic action of the loading dose of P-TZTP administered might have had pharmacological effects, the apparent inhibition might have resulted from reduced delivery rather than competition with receptor-binding. Therefore, we examined the effects of P-TZTP or FP-TZTP administration on cerebral blood flow (CBF) measured by the [(14)C]iodoantipyrine method and laser-Doppler flowmetry in rats. Statistically significant synchronous decreases in both CBF and mean arterial blood pressure (MABP) were observed within the first minute following administration. The decreases in both CBF and MABP were prevented by pretreatment with atropine methyl bromide (M-At), a peripheral muscarinic antagonist, and coadministration of M-At with either FP-TZTP or P-TZTP resulted in the same degree of inhibition of cerebral [(18)F]FP-TZTP-uptake 30 min after administration as observed without M-At. Also, with programmed infusions designed to produce constant arterial concentrations of [(18)F]FP-TZTP and FP-TZTP, which avoid changes in CBF, significant inhibition of [(18)F]FP-TZTP-binding by FP-TZTP was observed. These results indicate that inhibition of [(18)F]FP-TZTP-binding in the brain by P-TZTP or FP-TZTP in vivo occurs independently of their effects on CBF. The methods employed here may also be of interest to evaluate physiological effects of blocking agents utilized to validate other radiopharmaceuticals.
authors.affiliation: Positron Emission Tomography Department, Clinical Center, NIMH, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Shimoji
authors.forename: Takanori
authors.initials: T
authors.lastname: Esaki
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Itoh
authors.forename: Laura
authors.initials: L
authors.lastname: Ravasi
authors.forename: Michelle
authors.initials: M
authors.lastname: Cook
authors.forename: Jane
authors.initials: J
authors.lastname: Jehle
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Jagoda
authors.forename: Dale O
authors.initials: DO
authors.lastname: Kiesewetter
authors.forename: Kathleen
authors.initials: K
authors.lastname: Schmidt
authors.forename: Louis
authors.initials: L
authors.lastname: Sokoloff
authors.forename: William C
authors.initials: WC
authors.lastname: Eckelman
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives*; D001286:Atropine Derivatives / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000503:physiopathology; D002250:Carbon Radioisotopes; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D004347:Drug Interactions / Q000502:physiology; D005462:Fluorine Radioisotopes / Q000378:metabolism; D017078:Laser-Doppler Flowmetry; D008297:Male; D018721:Muscarinic Agonists / Q000378:metabolism / Q000493:pharmacokinetics; D011725:Pyridines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley; D043585:Receptor, Muscarinic M2 / Q000172:deficiency* / Q000187:drug effects; D013830:Thiadiazoles; D013844:Thiazoles / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C481718:3-(3-(propylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine; D001286:Atropine Derivatives; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D018721:Muscarinic Agonists; D011725:Pyridines; D043585:Receptor, Muscarinic M2; D013830:Thiadiazoles; D013844:Thiazoles; C006649:methylatropine; C115177:FP-TZTP; D000983:Antipyrine; C008135:iodoantipyrine