title: 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.affiliation: Department of Radiology, Indiana University School of Medicine, 1345 West 16th Street, L3-208, Indianapolis, IN 46202, USA.
authors.forename: Mingzhang
authors.initials: M
authors.lastname: Gao
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Kathy D
authors.initials: KD
authors.lastname: Miller
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
authors.forename: Qi-Huang
authors.initials: QH
authors.lastname: Zheng
mesh_terms: D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology; D002250:Carbon Radioisotopes / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D011960:Receptors, Estrogen / Q000378:metabolism*; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013194:Staining and Labeling; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D002250:Carbon Radioisotopes; D008024:Ligands; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D044005:Tetrahydroisoquinolines