Synthesis and evaluation of I-125 quinolinone analogues as potential oxytocin receptor biomarkers

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 k_i 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