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Aromatase (an enzyme that converts androgens to estrogens) in the brain is involved in neuroprotection, synaptic plasticity, and regulation of sexual and emotional behaviors. To investigate the physiologic and pathologic importance of aromatase in the brain, including in humans, we here report the development of a novel PET probe for aromatase, 11 C-cetrozole, which allows noninvasive quantification of aromatase expression. Methods: 11 C-cetrozole was synthesized by the C-11 C-methylation method developed by our group. In vitro autoradiography of frozen sections and a binding study with rat brain homogenates were conducted to demonstrate the specific binding and the dissociation constant. PET studies with anesthetized rhesus monkeys were performed to analyze the dynamics in the brain. Results: In vitro and in vivo studies using 11 C-cetrozole showed its superiority in brain aromatase imaging in terms of specificity and selectivity, compared with previously developed 11 C-vorozole. PET studies showed that 11 C-cetrozole had a higher signal-to-noise ratio, providing a sharper image than 11 C-vorozole, because the radioactive metabolite of 11 C-vorozole was taken up into the brain. High specific binding of 11 C-cetrozole was observed in the amygdala and hypothalamus, and we also noted binding in the nucleus accumbens of rhesus monkeys for the first time. Conclusion: These results suggest that PET imaging with newly developed 11 C-cetrozole is suitable for quantifying the expression of brain aromatase in vivo, possibly providing critical information regarding the functional roles of aromatase in human neurologic and emotional disorders.

P-glycoprotein (P-gp) plays a pivotal role in limiting the penetration of xenobiotic compounds into the brain at the blood-brain barrier (BBB), where its expression increases with maturation in rats. We investigated developmental changes in P-gp function in the BBB of nonhuman primates using PET with R-11 C-verapamil, a PET radiotracer useful for evaluating P-gp function. In addition, developmental changes in the brain penetration of 11 C-oseltamivir, a substrate for P-gp, was investigated as practical examples. Methods: PET studies in infant (age, 9 mo), adolescent (age, 24-27 mo), and adult (age, 5.6-6.6 y) rhesus monkeys (Macaca mulatta) were performed with R-11 C-verapamil and also with 11 C-oseltamivir. Arterial blood samples and PET images were obtained at frequent intervals up to 60 min after administration of the PET tracer. Dynamic imaging data were evaluated by integration plots using data collected within the first 2.5 min after tracer administration. Results: R-11 C-verapamil rapidly penetrated the brain, whereas the blood concentration of intact R-11 C-verapamil decreased rapidly in all subjects. The maximum brain uptake in infant (0.033% 6 0.007% dose/g of brain) and adolescent (0.020% 6 0.002% dose/ g) monkeys was 4.1-and 2.5-fold greater, respectively, than uptake in adults (0.0082% 6 0.0007% dose/g). The clearance of brain R-11 C-verapamil uptake in adult monkeys was 0.056 6 0.010 mL/min/g, significantly lower than that in infants (0.11 6 0.04 mL/min/g) and adolescents (0.075 6 0.023 mL/min/g). 11 C-oseltamivir showed little brain penetration in adult monkeys, with a clearance of R-11 C-verapamil uptake of 0.0072 and 0.0079 mL/min/g, slightly lower than that in infant (0.0097 and 0.0104 mL/min/g) and adolescent (0.0097 and 0.0098 mL/min/g) monkeys. Conclusion: These results suggest that P-gp function in the BBB changes with development in rhesus monkeys, and this change may be closely related to the observed difference in drug responses in the brains of children and adult humans.

Aromatase, an enzyme that converts androgens to estrogens, has been reported to be involved in several brain functions, including synaptic plasticity, neurogenesis, neuroprotection, and regulation of sexual and emotional behaviours in rodents, pathophysiology of Alzheimer’s disease and autism spectrum disorders in humans. Aromatase has been reported to be involved in aggressive behaviours in genetically modified mice and in personality traits by genotyping studies on humans. However, no study has investigated the relationship between aromatase in living brains and personality traits including aggression. We performed a positron emission tomography (PET) study in 21 healthy subjects using 11C-cetrozole, which has high selectivity and affinity for aromatase. Before performing PET scans, subjects answered the Buss-Perry Aggression Questionnaire and Temperament and Character Inventory to measure their aggression and personality traits, respectively. A strong accumulation of 11C-cetrozole was detected in the thalamus, hypothalamus, amygdala, and medulla. Females showed associations between aromatase levels in subcortical regions, such as the amygdala and supraoptic nucleus of the hypothalamus, and personality traits such as aggression, novelty seeking, and self-transcendence. In contrast, males exhibited associations between aromatase levels in the cortices and harm avoidance, persistence, and self-transcendence. The association of aromatase levels in the thalamus with cooperativeness was common to both sexes. The present study suggests that there might exist associations between aromatase in the brain and personality traits. Some of these associations may differ between sexes, while others are likely common to both.