title: The synthesis and preclinical evaluation in rhesus monkey of [¹⁸F]MK-6577 and [¹¹C]CMPyPB glycine transporter 1 positron emission tomography radiotracers.
abstract: 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. [¹¹C]CMPyPB was synthesized by the alkylation of a 3-hydroxypyridine precursor using [¹¹C]MeI, and [¹⁸F]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 [¹⁸F]MK-6577 showed a large specific signal and reversible binding. In vitro autoradiographic studies with [¹⁸F]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, [¹⁸F]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.
authors.affiliation: Discovery Imaging, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. terence_hamill@merck.com
authors.forename: Terence G
authors.initials: TG
authors.lastname: Hamill
authors.forename: Waisi
authors.initials: W
authors.lastname: Eng
authors.forename: Andrew
authors.initials: A
authors.lastname: Jennings
authors.forename: Richard
authors.initials: R
authors.lastname: Lewis
authors.forename: Steven
authors.initials: S
authors.lastname: Thomas
authors.forename: Suzanne
authors.initials: S
authors.lastname: Wood
authors.forename: Leslie
authors.initials: L
authors.lastname: Street
authors.forename: David
authors.initials: D
authors.lastname: Wisnoski
authors.forename: Scott
authors.initials: S
authors.lastname: Wolkenberg
authors.forename: Craig
authors.initials: C
authors.lastname: Lindsley
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Sanabria-Bohórquez
authors.forename: Shil
authors.initials: S
authors.lastname: Patel
authors.forename: Kerry
authors.initials: K
authors.lastname: Riffel
authors.forename: Christine
authors.initials: C
authors.lastname: Ryan
authors.forename: Jacquelynn
authors.initials: J
authors.lastname: Cook
authors.forename: Cyrille
authors.initials: C
authors.lastname: Sur
authors.forename: H Donald
authors.initials: HD
authors.lastname: Burns
authors.forename: Richard
authors.initials: R
authors.lastname: Hargreaves
mesh_terms: D000818:Animals; D001549:Benzamides / Q000097:blood / Q000138:chemical synthesis*; D002250:Carbon Radioisotopes / Q000097:blood; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005462:Fluorine Radioisotopes / Q000097:blood; D050487:Glycine Plasma Membrane Transport Proteins / Q000097:blood* / Q000378:metabolism; D006801:Humans; D008253:Macaca mulatta; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines / Q000097:blood / Q000138:chemical synthesis*; D013449:Sulfonamides / Q000097:blood / Q000138:chemical synthesis*
chemical_list: D001549:Benzamides; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D050487:Glycine Plasma Membrane Transport Proteins; C000599710:MK-6577; D011725:Pyridines; D013449:Sulfonamides; C023500:3-hydroxypyridine; C083126:2-chloropyridine