Synthesis and in vivo evaluation of [123I]melanin-targeted agents

This study reports the synthesis, [123I]radiolabeling, and biological profile of a new series of iodinated compounds for potential translation to the corresponding [131I]radiolabeled compounds for radionuclide therapy of melanoma. Radiolabeling was achieved via standard electrophilic iododestannylation in 60–90% radiochemical yield. Preliminary SPECT imaging demonstrated high and distinct tumor uptake of all compounds, as well as high tumor-to-background ratios compared to the literature compound [123I]4 (ICF01012). The most favorable compounds ([123I]20, [123I]23, [123I]41, and [123I]53) were selected for further biological investigation. Biodistribution studies indicated that all four compounds bound to melanin containing tissue with low in vivo deiodination; [123I]20 and [123I]53 in particular displayed high and prolonged tumor uptake (13% ID/g at 48 h). [123I]53 had the most favorable overall profile of the cumulative uptake over time of radiosensitive organs. Metabolite analysis of the four radiotracers found [123I]41 and [123I]53 to be the most favorable, displaying high and prolonged amounts of intact tracer in melanin containing tissues, suggesting melanin specific binding. Results herein suggest that compound [123I]53 displays favorable in vivo pharmacokinetics and stability and hence is an ideal candidate to proceed with further preclinical [131I] therapeutic evaluation. ©2015, American Chemical Society

Keywords

Synthesis, Tracer techniques, Radiopharmaceuticals, Therapy, Melanomas, Single photon emission computed tomography, Neoplasms, Melanin, Australia, Iodine 123

Citation

Roberts, M. P., Nguyen, V., Ashford, M. E., Berghofer, P., Wyatt, N. A., Krause-Heuer, A. M., Pham, T. Q., Taylor, S. R., Hogan, L., Jiang, C. D., Fraser, B. H., Lengkeek, N. A., Matesic, L., Grégoire, M. C., Denoyer, D., Hocks, R. J., Katsifis, A., & Greguric. I. (2015). Synthesis and in vivo evaluation of [123I] melanin-targeted agents. Journal of Medicinal Chemistry, 58(15), 6214-6224. doi:10.1021/acs.jmedchem.5b00777