The synthesis and preclinical evaluation in rhesus monkey of [¹⁸F]MK-6577 and [¹¹C]CMPyPB glycine transporter 1 positron emission tomography radiotracers.
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.
Hamill
Terence G
TG
Discovery Imaging, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. terence_hamill@merck.com
Eng
Waisi
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Jennings
Andrew
A
Lewis
Richard
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Thomas
Steven
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Wood
Suzanne
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Street
Leslie
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Wisnoski
David
D
Wolkenberg
Scott
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Lindsley
Craig
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Sanabria-Bohórquez
Sandra M
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Patel
Shil
S
Riffel
Kerry
K
Ryan
Christine
C
Cook
Jacquelynn
J
Sur
Cyrille
C
Burns
H Donald
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Hargreaves
Richard
R
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*
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