Abstract
Aromatase is an estrogen synthetic enzyme that plays important roles in brain functions. To quantify aromatase expression in the brain by positron emission tomography (PET), we had previously developed [(11)C]cetrozole, which showed high specificity and affinity. To develop more efficient PET tracer(s) for aromatase imaging, we synthesized three analogs of cetrozole. We synthesized meta-cetrozole, nitro-cetrozole, and iso-cetrozole, and prepared the corresponding (11)C-labeled tracers. The inhibitory activities of these three analogs toward aromatase were evaluated using marmoset placenta, and PET imaging of brain aromatase was performed using the (11)C-labeled tracers in monkeys. The most promising analog in the monkey study, iso-cetrozole, was evaluated in the human PET study. The highest to lowest inhibitory activity of the analogs toward aromatase in the microsomal fraction from marmoset placenta was in the following order: iso-cetrozole, nitro-cetrozole, cetrozole, and meta-cetrozole. This order showed good agreement with the order of the binding potential (BP) of each (11)C-labeled analog to aromatase in the rhesus monkey brain. A human PET study using [(11)C]iso-analog showed a similar distribution pattern of binding as that of [(11)C]cetrozole. The time-activity curves showed that elimination of [(11)C]iso-cetrozole from brain tissue was faster than that of (11)C-cetrozole, indicating more rapid metabolism of [(11)C]iso-cetrozole. [(11)C]Cetrozole has preferable metabolic stability for brain aromatase imaging in humans, although [(11)C]iso-cetrozole might also be useful to measure aromatase level in living human brain because of its high binding potential.