Abstract
1503
Objectives Development of PET or SPECT radioligands for oxytocin receptors of the brain would be ideal for psychopharmacological studies of human and non-human primates in understanding the neurobiological mechanisms underlying the behavioral effects of the oxytocin receptor system. The compounds [125I]-(E)-1-(1-(2-(2-((3-iodoallyl)oxy)-4-((1-(methylsulfonyl)piperidin-4-yl)oxy)phenyl)acetyl)piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (1) and [125I]-(Z)-1-(1-(2-(2-((3-iodoallyl)oxy)-4-((1-(methylsulfonyl)piperidin-4-yl)oxy)phenyl)acetyl)piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one (2) and their cold reference standards were synthesized and evaluated as potential PET or SPECT radioligands.
Methods Two tributylstannyl precursors for iodination, (E) and (Z)-1-(1-(2-(4-((1-(methylsulfonyl)piperidin-4-yl)oxy)-2-((3-(tributylstannyl)allyl)oxy)phenyl)acetyl)piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one were synthesized in twelve steps. Iodination was performed with [125I]- sodium iodide in the presence of H2O2 and HCl. In vitro autoradiography on prairie vole brain slices and lipophilicity measurements were performed with 1 and 2. Competitive binding assays were performed in vitro using prairie vole brain slices, the cold standard of 1, and selective, high-affinity I-125 labeled oxytocin or vasopressin peptides.
Results Compounds 1 and 2 were synthesized with radiochemical yields of 59% and 16% respectively with radiochemical purities ranging from 92.7 - 96%. The log P values were 2.36 for 1 and 2.18 for 2. Autoradiography data confirmed binding to the oxytocin receptor in the nucleus accumbens. Compound 1 outcompeted peptides for the oxytocin and vasopressin receptors and both ki values are being confirmed through additional binding assays.
Conclusions Compounds 1 and 2 displayed similar characteristics in binding specificity and selectivity. Lipophilicity was optimal for penetration to the brain. Both structures are viable candidates for further in vivo research.
Research Support NSF IBN-N876754 R0016