| Radioiodinated agents ranging in size from drugs to antibodies are used in many applications, including binding assays, autoradiography, imaging, and targeted therapeutics. Receptors are the current frontier for drug targets and will be the next frontier in imaging if tools with sufficient selectivity and potency can be developed to distinguish between emerging subpopulations of targets. Thus, a need exists for mild chemistries, compatible with complex molecules, for many transformations, including late-stage, site-selective incorporation of radioactive isotopes. Halogen exchange conditions are harsh due to high temperatures. Oxidative conditions can lead to uncontrolled incorporation into multiple sites, as well as possible damage to the structure via oxidation. Prosthetic groups are bulky, and some, like Bolton-Hunter, mask charges that could be important for selectivity and potency. Two radioiodination precursors that address these issues are the diazonium and the trialkylstannane. Diazonium formation is mild, and because the iodination reaction is nucleophilic, harsh oxidative conditions are not needed. Iodination via trialkylstannanes proceeds electrophilically, but at a much faster rate, reducing oxidative damage by reducing reaction time. Both methods incorporate radioiodine in a controlled, site-selective fashion. By experimenting with the catalyst ligands in both of these scenarios, we were able to improve their utility. By reducing the nucleophilicity of the copper ligand in the radioiodine dediazotization of a fully-deprotected endogenous opioid peptide, a-neoendorphin, we increased the radiochemical yield 10-fold, to approximately 30%. By altering the palladium ligands, we were able to utilize ambient conditions in the tributylstannylation of many deprotected, complex drug-like molecules. Some of these compounds we were unable to form in one step under harsher conditions, such as the semi-synthetic opioid drug, IBNtxA, and the sigma receptor antagonist, IPAG. To the best of our knowledge, this is the first account of stannylated IPAG or p-iodo-clonidine, as well as the first account of a radioiodinated a-neoendorphin analog. In conclusion, we have created site-selective, deprotected radioiodination precursors on peptides and small molecules via mild conditions. These precursors are also amenable to many other chemically useful transformations, including halogenations, radiohalogenations, and carbon-carbon bond forming reactions. |
