Synthesis Of Water-Soluble Radioiodonated (～(125)I) Quinazolinone Derivatives For Antibody-Directed Enzyme Prodrug Therapy

This paper mainly synthesis of a new water-soluble radiolabeled prodrug Ammonium-2-(2' -phosphoryloxyphpheny)-6-iodo-4(3H)-quinazolinne by many steps from basic chemical anthranilic acid, which is converted to a water-insoluble radiolabeled drug by the action of alkaline phosphatase for ADEPT (antibody-directed enzyme prodrug therapy).when The prodrug react with special enzyme on the surface of tumour,the prodrug changes to therapeutic drug and then pervades into tumour tissue and the radioactive I25I will use it radiancy to kll the tumour cell.ADEPT approach for the treatment of cancer has attracted considerable interest since the concept was introduced over a decade ago by Bagshawe and Senter[1]. To best of our knowledge, targeting of radiotherapeutic prodrug with ADEPT system has never been reported121. To test the concept, we choose to use radiolabeled Ammonium 2-(2' -Phosphoryloxyphenyl)-6-idio-4-(3H)-quinazolinone which is derivative of quinazolinone dye as the prodrug substrates. In 1994 Haugland131 et al described a class of novel fluorescent precipitating substrates made form quinazolinones for detecting cell-associated enzyme activity. When the enzyme acts on the substrate, a highly fluorescent product that is insoluble in aqueous system is formed. We would like to use a similar approach to synthesis a water-soluble radiolabeled molecule that is a substrate for alkaline phosphatase. Inthe presence of this enzyme, the molecule is hydrolyzed to a water-insoluble radioactive moity that precipitates in aqueous solution. We plan to localize this molecule within tumors following the administration of an anti-body-alkaline phosphatase conjugate. The radiolabeled precipitate will be trapped within the tumor mass and should lead to protracted irradiation of tumor cells. I optimize the way of synthesis compound and succeed in synthesis the compound we want.We have synthesised the water-soluble Chemical compound of radiolabeled (125I) Ammonium 2-(2' -Phosphoryloxyphenyl)-6-idio-4-(3H)-quinazolinone by many steps and we have demonstrated that the compound can convert to 2-(2' -Phosphoryloxyphenyl)-6-idio-4-(3H)-quinazolinone which is water-insoluble when incubated with alkaline phosphatase.That's our research proposal to develop a novel method that enables the active concentration of the therapeutic radionuclides within the extracellular space of tumor.We use tributylstannyl to active organic compound in the process of labelling and proved to be good.