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Inhibition of [ 18 F]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
Author(s) -
Shimoji Kazuaki,
Esaki Takanori,
Itoh Yoshiaki,
Ravasi Laura,
Cook Michelle,
Jehle Jane,
Jagoda Elaine M.,
Kiesewetter Dale O.,
Schmidt Kathleen,
Sokoloff Louis,
Eckelman William C.
Publication year - 2003
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.10257
Subject(s) - in vivo , agonist , muscarinic acetylcholine receptor , chemistry , pharmacology , medicine , receptor , biochemistry , biology , microbiology and biotechnology
[ 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. Synapse 50:151–163, 2003. Published 2003 Wiley‐Liss, Inc.