New carbon-11 labeled dual aromatase-steroid sulfatase inhibitors for PET imaging of aromatase and sulfatase in breast cancer

Objectives Aromatase and steroid sulfatase are particularly attractive targets in the treatment of estrogen receptor positive breast cancer and the development of enzyme-based cancer imaging agents for PET. A novel series of sulfamate derivatives have been recently developed as potent dual aromatase-steroid sulfatase inhibitors (DASIs). This study was designed to develop carbon-11 labeled DASIs as new PET cancer imaging agents.

Methods Unlabeled sulfamate derivatives and their hydroxyl precursors were synthesized from substituted benzaldehydes. The target tracers 5-(((4-cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)-2-[¹¹C]methoxyphenyl sulfamate, 4-(((4-cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)-2-[¹¹C]methoxyphenyl sulfamate and 2-chloro-4-(((4-cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)-2-[¹¹C]methoxyphenyl sulfamate were prepared from their corresponding precursors 5-(((4-cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)-2-hydroxyphenyl sulfamate, 4-(((4-cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)-2-hydroxyphenyl sulfamate and 2-chloro-4-(((4-cyanophenyl)(4H-1,2,4-triazol-4-yl)amino)methyl)-2-hydroxyphenyl sulfamate with [¹¹C]CH₃OTf under basic condition through O-[¹¹C]methylation and isolated by HPLC method.

Results The overall chemical yields for the target compounds in 6 steps were 3-12%. The overall chemical yields for the precursors in 8-9 steps were 1-3%. The radiochemical yields for the target tracers were 30-45%, decay corrected to EOB, based on [¹¹C]CO₂. The specific activity was 6.0-8.0 Ci/μmol at EOB.

Conclusions An efficient and convenient synthesis of carbon-11 labeled DASIs has been well-developed.

Research Support Breast Cancer Research Foundation and Susan G. Komen for the Cure.