Discovery of N-{(1S,2S)-2-(3-cyanophenyl)- 3-[4-(2-[18F]fluoroethoxy)phenyl]-1-methylpropyl}- 2-methyl-2-[(5-methylpyridin-2-yl)oxy]propanamide, a cannabinoid-1 receptor positron emission tomography tracer suitable for clinical use.
The discovery of a structurally distinct cannabinoid-1 receptor (CB1R) positron emission tomography tracer is described. Starting from an acyclic amide CB1R inverse agonist (1) as the lead compound, an efficient route to introduce 18F to the molecule was developed. Further optimization focused on reducing the lipophilicity and increasing the CB1R affinity. These efforts led to the identification of [18F]-16 that exhibited good brain uptake and an excellent signal-to-noise ratio in rhesus monkeys.
Liu
Ping
P
Lin
Linus S
LS
Hamill
Terence G
TG
Jewell
James P
JP
Lanza
Thomas J
TJ
Gibson
Raymond E
RE
Krause
Stephen M
SM
Ryan
Christine
C
Eng
Waisi
W
Sanabria
Sandra
S
Tong
Xinchun
X
Wang
Junying
J
Levorse
Dorothy A
DA
Owens
Karen A
KA
Fong
Tung M
TM
Shen
Chun-Pyn
CP
Lao
Julie
J
Kumar
Sanjeev
S
Yin
Wenji
W
Payack
Joseph F
JF
Springfield
Shawn A
SA
Hargreaves
Richard
R
Burns
H Donald
HD
Goulet
Mark T
MT
Hagmann
William K
WK
D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005462:Fluorine Radioisotopes; D006801:Humans; D008253:Macaca mulatta; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
D000577:Amides; D005462:Fluorine Radioisotopes; C523403:N-(2-(3-cyanophenyl)-3-(4-(2-fluoroethoxy)phenyl)-1-methylpropyl)-2-methyl-2-((5-methylpyridin-2-yl)oxy)propanamide; D011725:Pyridines; D019275:Radiopharmaceuticals; D043884:Receptor, Cannabinoid, CB1; D011994:Recombinant Proteins