Development of a radioligand for imaging V1a vasopressin receptors with PET

Abstract A series of vasopressin receptor V 1a ligands have been synthesized for positron emission tomography (PET) imaging. The lead compound (1 S, 5 R )- 1 ( (4-(1H-indol-3-yl)-3-methoxyphenyl) ((1 S ,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. (1 S, 5 R )- 1 was radiolabeled with 11 C for PET studies. [ 11 CH 3 ](1 S, 5 R )- 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 [ 11 CH 3 ](1 S, 5 R )- 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.