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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 [11C]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 11C-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 11C-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 11C-labeled analog to aromatase in the rhesus monkey brain. A human PET study using [11C]iso-analog showed a similar distribution pattern of binding as that of [11C]cetrozole. The time–activity curves showed that elimination of [11C]iso-cetrozole from brain tissue was faster than that of 11C-cetrozole, indicating more rapid metabolism of [11C]iso-cetrozole. [11C]Cetrozole has preferable metabolic stability for brain aromatase imaging in humans, although [11C]iso-cetrozole might also be useful to measure aromatase level in living human brain because of its high binding potential.
Highlights
Aromatase is an estrogen synthetic enzyme that plays important roles in brain functions
The distribution volume ratio (DVR) images of all tracers showed a similar distribution pattern, i.e., high binding of the tracers was observed in the amygdala, hypothalamus, and nucleus accumbens; the signal intensity was different (Fig. 2)
The inhibitory activity of the analogs including cetrozole toward aromatase in the microsomal fraction of marmoset placenta was in the following order: iso-cetrozole (IC50 = 0.68 nM), nitro-cetrozole (IC50 = 0.73), cetrozole (IC50 = 0.98), and meta-cetrozole (IC50 = 3.50)
Summary
Aromatase is an estrogen synthetic enzyme that plays important roles in brain functions. The inhibitory activities of these three analogs toward aromatase were evaluated using marmoset placenta, and PET imaging of brain aromatase was performed using the 11C-labeled tracers in monkeys. 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, nitrocetrozole, cetrozole, and meta-cetrozole This order showed good agreement with the order of the binding potential (BP) of each 11C-labeled analog to aromatase in the rhesus monkey brain. To develop more efficient PET tracer(s) for aromatase imaging in the human brain, we synthesized three analogs of cetrozole: meta-cetrozole, nitro-cetrozole[25] and iso-cetrozole[26] previously referred to as TMD-32227
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