Novel Metal Ion Based Estrogen Mimics for Molecular Imaging

76195-In the conventional bioconjugate approach to radioimaging, involving small molecule carriers such as steroids, one of the most vexing problems has been that the large size of the radionuclide metal complex greatly perturbs the physical property, receptor binding affinity, and membrane permeability of the resulting bioconjugate. In addition to steroid receptor binding, the efficacy of steroidal drugs depends equally on the ability to bind to sex hormone biding globulin (SHBG). Therefore, the design of any radiopharmaceutical must not only take into account receptor affinity but also SHBG binding capability. This project will develop radionuclide metal-ion-containing estrogen mimics for the in vivo imaging of estrogen receptor (ER) positive breast cancers. In particular, the efficacy of a prototypical 99mTc-based estrone mimic will be determined. Phase I will: (1) synthesize 99mTc-based N3S or N2S2 estrone mimics, (2) perform ER binding studies, (3) perform SHBG binding studies, and (4) perform metal complex stability studies. Phase II will carry out full structure-activity relationship studies and identify a lead clinical candidate. Commercial Applications and Other Benefits as described by the awardee: The estrogen-based, metal-substituted molecules should have great commercial potential in the diagnosis and treatment of breast cancer. Substituting suitable metals such as 99mTc, 94mTc, or 68Ga should provide compounds suitable for diagnostic radioimaging. Substituting ?-emitting nuclides such as 186Re, 188Re, or 153Sm should result in compounds suitable for radiotherapy.