Relationship of Structure to Biodistribution of Technetium Complexes. Tc/Re complexes for Sigma Receptor Studies in Oncology. Sigma 1 and sigma 2 binding sites are expressed in high density in a wide variety of human and rodent tumor cell lines. Technetium-99m (Tc-99m) radiopharmaceuticals are utilized widely in the clinical diagnosis and prognosis of disease. Tc-99m is generator produced, inexpensive, and available world-wide. It is ideal for imaging studies due to a favorable half-life (6.02 hr) and energy of the single gamma photon (140 KeV). In vivo detection of cancerous cells containing sigma receptors may be possible if high affinity, selective Tc-99m complexes can be identified. From the radionuclides considered for therapy, rhenium-186 (Re-186) and rhenium-188 (Re-188) possess suitable half lives and strong beta- emissions capable of delivering high doses to tissues. Both have a gamma photon (137 KeV, 9% and 155 KeV, 15%, respectively), making it possible to follow their biodistribution with the same scintigraphic equipment as used for Tc-99m. Therapeutic measures could be initiated upon substitution of Tc with either Re-186 or Re- 188. We propose to synthesize novel polyamine derivatives, based on high affinity compounds for the sigma- 1 and sigma- 2 binding sites, and prepare their corresponding Tc and Re complexes. Their biodistribution in mice in accord with normal distribution of sigma receptors will be assessed. Their affinity and specificity for the sigma-1 and sigma-2 binding sites will be assessed in vitro in guinea pig brain homogenates and rat liver homogenates, respectively. Ligands and complexes displaying high affinity (nM range) will be further assayed in vitro in selected cells lines. The most promising Tc complexes will be evaluated in tumor-bearing mice for diagnostic potential; and evaluation of the most promising Re complexes for their therapeutic value. Requirements for a Physician-sponsored IND will be completed on the compound(s) that display appropriate characteristics.
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