Development of a series of novel carbon‐11 labeled PDE10A inhibitors

Phosphodiesterase 10A (PDE10A) is a member of the PDE family of enzymes that degrades cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Our aim was to label a series of structurally related PDE10A inhibitors with carbon‐11 and evaluate them as potential positron emission tomography (PET) radioligands for PDE10A using nonhuman primates. The series consisted of seven compounds based on the 3‐(1H‐pyrazol‐5‐yl)pyridazin‐4(1H)‐one backbone. These compounds were selected from the initial larger library based on a number of parameters such as affinity, selectivity for hPDE10A in in vitro tests, lipophilicity, and on the results of multidrug resistance protein 1 (MDR1)‐LLCPK1 and the parallel artificial membrane permeability assays. Seven radioligands (KIT‐1, 3, 5, 6, 7, 9, and 12) were radiolabeled with carbon‐11 employing O‐methylation on the hydroxyl moiety using [¹¹C]methyl triflate. In vivo examination of each radioligand was performed using PET in rhesus monkeys; analysis of radiometabolites in plasma also was conducted using HPLC. All seven radioligands were labeled with high (>90%) incorporation of [¹¹C]methyl triflate into their appropriate precursors and with high specific radioactivity. Carbon‐11 labeled KIT‐5 and KIT‐6 showed high accumulation in the striatum, consistent with the known anatomical distribution of PDE10A in brain, accompanied by fast washout and high specific binding ratio. In particular [¹¹C]KIT‐6, named [¹¹C]T‐773, is a promising PET tool for further examination of PDE10A in human brain.