New synthesis and tritium labeling of a selective ligand for studying high-affinity γ-hydroxybutyrate (GHB) binding sites.
3-Hydroxycyclopent-1-enecarboxylic acid (HOCPCA, 1) is a potent ligand for the high-affinity GHB binding sites in the CNS. An improved synthesis of 1 together with a very efficient synthesis of [(3)H]-1 is described. The radiosynthesis employs in situ generated lithium trimethoxyborotritide. Screening of 1 against different CNS targets establishes a high selectivity, and we demonstrate in vivo brain penetration. In vitro characterization of [(3)H]-1 binding shows high specificity to the high-affinity GHB binding sites.
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , 2100 Copenhagen, Denmark.
Stine B
SB
Vogensen
Aleš
A
Marek
Tina
T
Bay
Petrine
P
Wellendorph
Jan
J
Kehler
Christoffer
C
Bundgaard
Bente
B
Frølund
Martin H F
MH
Pedersen
Rasmus P
RP
Clausen
D000818:Animals; D001567:Benzocycloheptenes / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D002490:Central Nervous System / Q000378:metabolism*; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D004355:Drug Stability; D006885:Hydroxybutyrates / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D008297:Male; D008956:Models, Chemical; D015394:Molecular Structure; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013570:Synaptic Membranes / Q000378:metabolism; D014316:Tritium / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000737:chemistry / Q000378:metabolism
C586846:3-hydroxycyclopent-1-enecarboxylic acid; D001567:Benzocycloheptenes; D002264:Carboxylic Acids; D003517:Cyclopentanes; D006885:Hydroxybutyrates; D008024:Ligands; D014316:Tritium; C066471:NCS 382; C111420:4-hydroxybutyric acid; D005680:gamma-Aminobutyric Acid