Copper-Mediated Radioiodination Approach Using Aryl Boronic Acids And Its Application

Radioiodine(123I,124I,125I and 131I)labeled radiopharmaceuticals are widely used in nuclear medicine for disease diagnosis and therapy.However,in the past few decades,the radioiodination methods have been limited to halogen exchange method and electrophilic substitution labeling method,which using oxidizing agents to produce radioactive iodine and then occuring electrophilic substitution reaction with electron-rich aromatic compounds.To overcome the limitations of these traditional radioiodination methods,the aim of this research is to develop one new radioiodination method for the radioiodine labeling of small molecules,peptides,proteins and other bio-materials.The main research contents are as follows:Firstly,after a series of reaction conditions such as the types and chemical quantity of the catalyst and ligand,reaction time and substrate species were screened and optimized based on the Chan-Lam reaction,a novel copper-mediated radioiodination method using phenylboronic acids was successfully established.With the use of catalyst copper source like Cu2O,CuI,CuCl and the ligand 1,10-phenanthroline,metal-catalyzed oxidative coupling reaction between phenylboronic acid compounds and radioactive iodine ions can take place directly at room temperature.Compared with the traditional radioiodination methods,this method is technically simple,efficient,low-cost,with no need of using oxidizing agents to produce molecular iodine,and the radiolabeled product can be easily separated from the precursor to achieve high specific activity product,which can well overcome the shortcomings of traditional radioiodination methods.Secondly,based on this new kind radioiodination method,we prepared no carrier added I-MIBG(n.c.a.[*I-MIBG]).Phenylboronic acid precursor can be obtained by one-step chemical reaction and the radiochemical yield can reach more than 95%.Because the chemical polarity of the labeling product and the precursor are quite different,we can purify the labeling product just using one silica gel column and with no need using HPLC to obtain the n.c.a.['I-MIBG].By using this new radioiodination method,the precursor preparation,labeling and purification process are all significantly simplified.Finally,in order to extend this new radioiodination method to peptide,protein and other biological material radiodine labeling,we have successively developed a series of phenylboronic acid precursors containing carboxyl activated esters([*I]SIB),bicyclobutane structure,azide,biotin structure and amino group,and successfully prepared various heterobifunctional agents using this new radioiodination method.As one new kind heterobifunctional agent which can specifically react with thiol,131I-S8 has better stability in vitro and in vivo and better specific selectivity for thiol than traditional maleimide heterobifunctional agents.When both amino and thiol groups exist at the same time,it reacts with thiol only even heated to 60?.The results of biodistribution experiment further verified that 131I-S8 labeled RGD peptide has much better stability in vivo than that of product prepared by using traditional Iodogen methodAccording to this study,we developed one new copper-mediated radioiodination approach using phenylboronic acids,and a series of remarkable advantages make it possible to become a new radioiodination method with important practical application value,thus promoting the research progress and clinical application of the radioiodine labeling drugs.