PET of Aromatase in Gastric Parietal Cells Using ¹¹C-Vorozole

Abstract

Aromatase is a rate-limiting enzyme for estrogen biosynthesis and has been implicated in pathophysiological states of various diseases via estrogen production. This enzyme is known to be widely distributed in extragonadal and gonadal tissues including the stomach. In contrast to circulating estrogen, the functional role of gastric aromatase/estrogen has not been elucidated in detail, because there is no efficient methodology to investigate spatiotemporal changes of gastric aromatase/ estrogen in vivo. Recently, (S)-11 C-6-[(4-chlorophenyl)(1H-1,2,4-triazole-1-yl)methyl]-1-methyl-1H-benzotriazole ( 11 Clabeled vorozole), based on a potent nonsteroidal aromatase inhibitor, has been developed as a tracer to investigate aromatase distribution in living animals and humans using a noninvasive PET technique. In the present study, we investigated gastric aromatase expression by means of PET with 11 C-vorozole. Methods: After bolus injection of 11 C-vorozole into the tail vein, emission scans were obtained for 90 min on male and female rats under isoflurane anesthesia. Displacement studies with unlabeled vorozole and autoradiographic analysis were conducted for demonstration of specific binding. Immunohistochemistry was performed to confirm aromatase expression. Results: PET scans revealed that 11 C-vorozole highly accumulated in the stomach and adrenal glands. Displacement studies and autoradiography demonstrated that aromatase was expressed in the stomach but that the accumulation of 11 C-vorozole in the adrenal glands might be through nonspecific binding. Immunohistochemical analysis revealed that aromatase is expressed in gastric parietal cells but not in adrenal glands. Moreover, the accumulation of 11 C-vorozole in the stomach was significantly increased in fatigued rats. Conclusion: These results suggest that the 11 C-vorozole PET technique is a useful tool for evaluation of gastric aromatase dynamics in vivo, which may provide important information for understanding the molecular mechanisms of gastric aromatase/estrogenrelated pathophysiological processes and for the development of new drugs.

In vivo visualization of aromatase in animals and humans

“…Prominent liver uptake was also seen across species. However, the high uptake in rat stomach reported by Ozawa et al (2011) was not seen in baboons or humans. Tracer uptake in the majority of most other peripheral organs, including bone, kidney, muscle, heart and lung, was uniformly low across species.…”

“…In vivo visualization of aromatase in rats was performed using microPET and [ 11 C]-vorozole (Ozawa et al, 2011; Kim et al, 2009). High accumulation of [ 11 C]vorozole was detected in the stomach and the adrenal glands.…”

“…Displacement studies and autoradiography demonstrated that aromatase was expressed in the stomach but that the accumulation of [ 11 C]vorozole in the adrenal glands might represent nonspecific binding. Interestingly, the accumulation of [ 11 C]vorozole in the stomach was significantly increased in fatigued rats (Ozawa et al 2011). The high uptake in the ovaries is to be expected since the ovaries are the main site of peripheral estrogen production.…”

Targeting breast cancer through its microenvironment: Current status of preclinical and clinical research in finding relevant targets

“…In the future, aromatase imaging might be possible. An aromatase PET tracer is in preclinical development (Ozawa et al, 2011;Takahashi et al, 2014), although not for the purpose of breast cancer research. ER expression can be determined by 18 F-fluoroestradiol ( 18 F-FES) PET.…”

Estrogens and Gastroparesis: A Clinical Relevance

“…Recent studies have also demonstrated that stomach parietal cells abundantly express aromatase, a key enzyme for the production of sex steroids, and catalyze the final step of the biosynthetic pathway of estrogen [16]. Though gastric aromatase/estrogen has been implicated in several pathophysiological states, such as liver regeneration and feminization, by acting as a local regulator of the gastrohepatic axis, its functional role has still to be elucidated.…”