Synthesis, radiolabeling and preliminary in vivo evaluation of multimodal radiotracers for PET imaging and targeted radionuclide therapy of pigmented melanoma

Melanin pigment represents an attractive target to address specific treatment to melanoma cells, such as cytotoxic radionuclides. However, less than half of the patients have pigmented metastases. Hence, specific marker is required to stratify this patient population before proceeding with melanin-targeted radionuclide therapy. In such a context, we developed fluorinated analogues of a previously studied melanin-targeting ligand, N-(2-diethylaminoethyl)-6-iodoquinoxaline-2-carboxamide (ICF01012). These latter can be labeled either with 18F or 131I/125I for positron emission tomography imaging (melanin-positive patient selection) and targeted radionuclide therapy purposes. Here we describe the syntheses, radiosyntheses and preclinical evaluations on melanoma-bearing mice model of several iodo- and fluoro(hetero)aromatic derivatives of the ICF01012 scaffold. After preliminary planar gamma scintigraphic and positron emission tomography imaging evaluations, [125I]- and [18F]-N-[2-(diethylamino)ethyl]-4-fluoro-3-iodobenzamides ([125I]4, [18F]4) were found to be chemically and biologically stable with quite similar tumor uptakes at 1 h p.i. (9.7 ± 2.6% ID/g and 6.8 ± 1.9% ID/g, respectively). [Display omitted] •New iodinated and fluorinated heteroaromatic analogues of ICF01012 were synthesized.•125I or 18F-labeled analogues were screened using planar scintigraphic or PET imaging.•Specific tumor uptakes were observed for 125I/18F-4, 125I/18F-17 and 125I/18F-71.•Moderated to high radiodefluorination was observed for 18F-9, 18F-17 and 18F-71.