Optimization by Experimental Design of Precursor Synthesis and Radiolabeling of 2-Iodo-L-Phenylalanine, a Novel Amino Acid for Tumor Imaging

Various radiolabeled amino acids show promising results in tumor detection, as applied in the management of cancer patients. We synthesized the precursor 2-iodo-L-phenylalanine for easier kit labeling of [123/125I]- 2-iodo-L-phenylalanine, using the Cu1+-assisted nucleophilic halogen exchange. Precursor synthesis was optimized by experimental design: Eight parameters were initially screened by a quarter fractional design. The resulting most important parameters (i.e., temperature, CuSO4, NaI) were further optimized using a full three-factor, three-level factorial design. The final conclusion for the optimal values for temperature, reaction time, and concentration of 2-bromo-L-phenylalanine, NaI, CuSO4, SnSO4, C6H6O7, and C7H6O4 were 180°C, 24 hours, 61 mM, 485 mM, 10 mM, 90 mM, 90 mM, and 100 mM, respectively. The yield was increased from 39% to consistently more than 74% 2-iodo-L-phenylalanine. Structure confirmation and quality control was performed by 1H-NMR, mass spectroscopy (MS), and high-performanc...