Development of a radioligand for imaging V_1a vasopressin receptors with PET

A series of vasopressin receptor V_1a ligands have been synthesized for positron emission tomography (PET) imaging. The lead compound (1S,5R)-1 ((4-(1H-indol-3-yl)-3-methoxyphenyl) ((1S,5R)-1,3,3-trimethyl-6-azabicyclo[3.2.1]octan-6-yl)methanone) and its F-ethyl analog 6c exhibited the best combination of high binding affinity and optimal lipophilicity within the series. (1S,5R)-1 was radiolabeled with ¹¹C for PET studies. [¹¹CH₃](1S,5R)-1 readily entered the mouse (4.7% ID/g tissue) and prairie vole brains (∼2% ID/g tissue) and specifically (30–34%) labeled V_1a receptor. The common animal anesthetic Propofol significantly blocked the brain uptake of [¹¹CH₃](1S,5R)-1 in the mouse brain, whereas anesthetics Ketamine and Saffan increased the uptake variability. Future PET imaging studies with V_1a radiotracers in non-human primates should be performed in awake animals or using anesthetics that do not affect the V_1a receptor.