Astatine-211, an alpha-emitter with a half-life of 7.2 h, is among the most promising radionuclides under development as a radiopharmaceutical for the treatment of malignant disease because of its convenient half-life and the shorter penetration of its alpha emissions. A pivotal issue in designing an optimal radiopharmaceutical remains the choice of the chemistry to conjugate the redionuclide to the carrier molecule. The linker must hold the radionuclide firmly so that there is no premature release of the isotope in vivo. A number of acylation agents for At-211 labeling of proteins, peptides and small molecules, have been developed over the last ten years. Although these labeling reagents have shown encouraging results intact mAbs and have allowed for the initiation of the first clinical trials involving At-211 in our instituition, questions remain about the unusually high accumulation of At-211 in some tissues, such as lings and spleen, when antibody fragments or small molecules are used. Clearly, new and improved techniques for At-211 labeling of smaller radionuclide carriers are urgently needed. The objective of this proposal is the preparation and evaluation of higher oxidation states At-211 labeling as a novel approach in the preparation of At-211 radiopharmaceuticals. To this end there are four specific aims: i) to develop the optimal chemistry for isolation and concentration of higher oxidation states At-211; 2) to investigate the in vitro and in vivo biological behavior of higher oxidation states At-211; 3) to synthesize, identify and purify organic molecular carriers radiolabeled with higher oxidation states At-211; and 4) to investigate the in vitro and in vivo biological stability of organic molecular carriers radiolabeled with higher oxidation states At-211. The in vivo biological behavior of all At-211 inorganic species and radiolabeled small organic molecules will be evaluated in BALB/c mice.
