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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 iododestannyl...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2015-08, Vol.58 (15), p.6214-6224
Main Authors: Roberts, Maxine P, Nguyen, Vu, Ashford, Mark E, Berghofer, Paula, Wyatt, Naomi A, Krause-Heuer, Anwen M, Pham, Tien Q, Taylor, Stephen R, Hogan, Leena, Jiang, Cathy D, Fraser, Benjamin H, Lengkeek, Nigel A, Matesic, Lidia, Gregoire, Marie-Claude, Denoyer, Delphine, Hicks, Rodney J, Katsifis, Andrew, Greguric, Ivan
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Language:English
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b00777