Synthesis and preliminary biological evaluation of new carbon-11 labeled tetrahydroisoquinoline derivatives as SERM radioligands for PET imaging of ER expression in breast cancer.

Abstract

The estrogen receptors (ERs) are attractive targets in the treatment of breast cancer and the development of receptor-based breast cancer imaging agents for diagnostic use in biomedical imaging technique positron emission tomography (PET). Tetrahydroisoquinoline derivatives are a class of selective estrogen receptor modulators (SERMs) with high binding affinity and specificity exhibiting up to 50 folds for ERalpha over ERbeta. New carbon-11 labeled tetrahydroisoquinoline derivatives, [11C]methyl 1-(2-(4-(2-(4-fluorophenyl)-6-hydroxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenoxy)ethyl)piperidine-4-carboxylate ([11C]10a) and [11C]methyl 1-(2-(4-(2-(4-chlorophenyl)-6-hydroxy-1-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenoxy)ethyl)piperidine-4-carboxylate ([11C]10b), have been first designed, synthesized and evaluated. The target tracers were prepared by O-[11C]methylation of their corresponding precursors using [11C]CH3OTf and isolated by solid-phase extraction (SPE) purification procedure in 40-60% radiochemical yields, which were decay corrected to the end of bombardment (EOB), based on [11C]CO2. The overall synthesis time was 15-20 min from EOB. The radiochemical purity was >99%, and specific activity was in a range of 74-111GBq/micromol at the end of synthesis (EOS). Preliminary findings from in vitro biological assay indicate that the synthesized derivatives displayed similar potencies in the MCF-7 human breast cancer cell line in comparison with 4-hydroxytamoxifen, a well-known potent SERM. These results encourage further in vivo evaluation of carbon-11 labeled tetrahydroisoquinoline derivatives as new potential SERM radioligands for PET imaging of ER expression in breast cancer.

• Authors: Mingzhang Gao, Min Wang, Kathy D Miller, George W Sledge, Qi-Huang Zheng
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 43 Issue 10 Pg. 2211-9 (Oct 2008) ISSN: 0223-5234 [Print] France
• PMID: 18272256 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carbon Radioisotopes
• Ligands
• Receptors, Estrogen
• Selective Estrogen Receptor Modulators
• Tetrahydroisoquinolines

Topics

• Breast Neoplasms (diagnostic imaging, metabolism, pathology)
• Carbon Radioisotopes (chemistry)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Design
• Gene Expression Regulation, Neoplastic
• Humans
• Ligands
• Positron-Emission Tomography
• Radiochemistry
• Receptors, Estrogen (metabolism)
• Selective Estrogen Receptor Modulators (chemical synthesis, chemistry, pharmacology)
• Staining and Labeling
• Tetrahydroisoquinolines (chemical synthesis, chemistry, pharmacology)