Modification of an iodinated peptide with µ-opioid receptor affinity to reduce lipophilicity [abstract]

Abstract

The di-iodinated peptide DMT-D-Ala-Phe-Phe (DAPP) was found to have high affinity and selectivity for µ-opioid receptors of cancer cells. Radioiodination of this peptide could aid in imaging of tumors; however, the molecule's high lipophilicity would not allow easy travel in vivo. In order to reduce lipophilicity but keep the µ-receptor affinity, two alternative peptides were produced using solid phase synthesis: DMT-D-Ala-Phe-Orn and DMT-Nva-Phe-Orn. Their structure and purity were evaluated using LCMS and amino acid analysis. To further reduce the lipophilicity, two methods for mono-iodination were investigated on Boc protected dimethyltyrosine (Boc-DMT). In the first, commonly accepted iodination method, N-iodosuccinamide (NIS) was used as the iodinating reagent. Two equivalents of NIS were reacted with Boc-DMT in phosphate buffer solution (pH 7.4). A mixture of mono- and di-iodinated products was produced, and the percent di-iodinated product increased with reaction time. The second iodination method used bis(pyridine)iodonium tetrafluoroborate (IPy2BF4) as the iodinating agent with tetrafluoroboric acid (HBF4) catalyst. Optimization of this method was done by varying the reaction time, solvent, and equivalents of IPy2BF4. The optimal conditions (those producing the most mono-iodinated products and least by-products) were found to be using 2 equivalents of IPy2BF4 for 5 minutes in methanol. The scale of the reaction did not affect the reaction speed or product distribution. After work up with water and ethyl acetate, the mono-iodinated Boc-DMT will be purified through column chromatography. The 2 new peptides should be synthesized again with the iodinated Boc-DMT. Lipophilicity of these new molecules should be tested. Mono-radio-iodination can be done using the same method, and biological evaluations of the molecules will be conducted.