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The synthesis and preclinical evaluation in rhesus monkey of [ 18 F]MK‐6577 and [ 11 C]CMPyPB glycine transporter 1 positron emission tomography radiotracers
Author(s) -
Hamill Terence G.,
Eng Waisi,
Jennings Andrew,
Lewis Richard,
Thomas Steven,
Wood Suzanne,
Street Leslie,
Wisnoski David,
Wolkenberg Scott,
Lindsley Craig,
SanabriaBohÓRquez Sandra M.,
Patel Shil,
Riffel Kerry,
Ryan Christine,
Cook Jacquelynn,
Sur Cyrille,
Burns H. Donald,
Hargreaves Richard
Publication year - 2011
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.20842
Subject(s) - in vivo , positron emission tomography , chemistry , glycine , preclinical imaging , radiochemistry , nuclear medicine , biochemistry , amino acid , biology , medicine , microbiology and biotechnology
Two positron emission tomography radiotracers for the glycine transporter 1 (GlyT1) are reported here. Each radiotracer is a propylsulfonamide‐containing benzamide and was labeled with either carbon‐11 or fluorine‐18. [ 11 C]CMPyPB was synthesized by the alkylation of a 3‐hydroxypyridine precursor using [ 11 C]MeI, and [ 18 F]MK‐6577 was synthesized by a nucleophilic aromatic substitution reaction using a 2‐chloropyridine precursor. Each tracer shows good uptake into rhesus monkey brain with the expected distribution of highest uptake in the pons, thalamus, and cerebellum and lower uptake in the striatum and gray matter of the frontal cortex. In vivo blockade and chase studies of [ 18 F]MK‐6577 showed a large specific signal and reversible binding. In vitro autoradiographic studies with [ 18 F]MK‐6577 showed a large specific signal in both rhesus monkey and human brain slices and a distribution consistent with the in vivo results and those reported in the literature. In vivo metabolism studies in rhesus monkeys demonstrated that only more‐polar metabolites are formed for each tracer. Of these two tracers, [ 18 F]MK‐6577 was more extensively characterized and is a promising clinical positron emission tomography tracer for imaging GlyT1 and for measuring GlyT1 occupancy of therapeutic compounds. Synapse, 2011. © 2010 Wiley‐Liss, Inc.