title: Comparative preclinical evaluation of68Ga-NODAGA and68Ga-HBED-CC conjugated procainamide in melanoma imaging.
abstract: Malignant melanoma is the most aggressive form of skin cancer. The early detection of primary melanoma tumors and metastases using non-invasive PET imaging determines the outcome of this disease. Previous studies have shown that benzamide derivatives (e.g. procainamide) conjugated with PET radionuclides specifically bind to melanin pigment of melanoma tumors.68Ga chelating agents can have high influence on physiological properties of68Ga labeled bioactive molecules, as was experienced during the application of HBED-CC on PSMA ligand. The aim of this study was to assess this concept in the case of the melanin specific procaindamide (PCA) and to compare the melanin specificity of68Ga-labeled PCA using HBED-CC and NODAGA chelators under in vitro and in vivo conditions. Procainamide (PCA) was conjugated with HBED-CC and NODAGA chelators and was labeled with Ga-68. The melanin specificity of68Ga-HBED-CC-PCA and68Ga-NODAGA-PCA was investigated in vitro and in vivo using amelanotic (MELUR and A375) and melanin containing (B16-F10) melanoma cell lines. Tumor-bearing mice were prepared by subcutaneous injection of B16-F10, MELUR and A375 melanoma cells into C57BL/6 and SCID mice. 21±2days after tumor cell inoculation and 90min after intravenous injection of the68Ga-labelledlabeled radiopharmacons whole body PET/MRI scans were performed.68Ga-NODAGA-PCA and68Ga-HBED-CC-PCA were produced with excellent radiochemical purity (98%). In vitro experiments demonstrated that after 30 and 90min incubation time68Ga-NODAGA-PCA uptake of B16-F10 cells was significantly (p≤0.01) higher than the68Ga-HBED-CC-conjugated PCA accumulation in the same cell line. Furthermore, significant difference (p≤0.01 and 0.05) was found between the uptake of melanin negative and positive cell lines using68Ga-NODAGA-PCA and68Ga-HBED-CC-PCA. In vivo PET/MRI studies using tumor models revealed significantly (p≤0.01) higher68Ga-NODAGA-PCA uptake (SUVmean: 0.46±0.05, SUVmax: 1.96±0.25,T/M ratio: 40.7±4.23) in B16-F10 tumors in contrast to68Ga-HBED-CC-PCA where the SUVmean, SUVmax and T/M ratio were 0.13±0.01, 0.56±0.11 and 11.43±1.24, respectively. Melanin specific PCA conjugated with NODAGA chelator showed higher specific binding properties than conjugated with HBED-CC. The chemical properties of the bifunctional chelators used for68Ga-labeling of PCA determine the biological behaviour of the probes. Due to the high specificity and sensitivity68Ga-labeled PCA molecules are promising radiotracers in melanoma imaging.
authors.affiliation: Department of Medical Imaging, Nuclear Medicine, University of Debrecen, Debrecen, Hungary; Scanomed LTD, Debrecen, Hungary. Electronic address: trencsenyi.gyorgy@med.unideb.hu.
authors.forename: György
authors.initials: G
authors.lastname: Trencsényi
authors.affiliation: Department of Medical Imaging, Nuclear Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Noémi
authors.initials: N
authors.lastname: Dénes
authors.affiliation: Scanomed LTD, Debrecen, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Nagy
authors.affiliation: Department of Medical Imaging, Nuclear Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Adrienn
authors.initials: A
authors.lastname: Kis
authors.affiliation: Department of Medical Chemisty, University of Debrecen, Debrecen, Hungary; MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Vida
authors.affiliation: Department of Medical Imaging, Nuclear Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Flóra
authors.initials: F
authors.lastname: Farkas
authors.affiliation: Department of Medical Imaging, Nuclear Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Judit P
authors.initials: JP
authors.lastname: Szabó
authors.affiliation: Department of Medical Chemisty, University of Debrecen, Debrecen, Hungary; MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, Hungary.
authors.forename: Tünde
authors.initials: T
authors.lastname: Kovács
authors.affiliation: Department of Medical Imaging, Nuclear Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Ervin
authors.initials: E
authors.lastname: Berényi
authors.affiliation: Scanomed LTD, Debrecen, Hungary.
authors.forename: Ildikó
authors.initials: I
authors.lastname: Garai
authors.affiliation: Department of Medical Chemisty, University of Debrecen, Debrecen, Hungary; MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen, Hungary; Research Center for Molecular Medicine, University of Debrecen, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Bai
authors.affiliation: Department of Dermatology, University of Debrecen, Debrecen, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Hunyadi
authors.affiliation: Department of Medical Imaging, Nuclear Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Kertész
mesh_terms: D000085:Acetates / Q000378:metabolism*; D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004492:Edetic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D005260:Female; D005710:Gallium Radioisotopes / Q000378:metabolism*; D006573:Heterocyclic Compounds, 1-Ring / Q000378:metabolism*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008546:Melanoma, Experimental / Q000000981:diagnostic imaging / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D049268:Positron-Emission Tomography / Q000379:methods; D011342:Procainamide / Q000378:metabolism*; D012878:Skin Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: C572723:1-(1,3-carboxypropyl)-4,7-carboxymethyl-1,4,7-triazacyclononane; D000085:Acetates; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; C075313:N,N'-bis(2-hydroxy-5-(ethylene-beta-carboxy)benzyl)ethylenediamine N,N'-diacetic acid; D004492:Edetic Acid; D011342:Procainamide
keywords: (68)Ga; HBED-CC; Melanoma; NODAGA; Positron emission tomography; Procainamide