title: Benefits of NOPO as chelator in gallium-68 peptides, exemplified by preclinical characterization of (68)Ga-NOPO-c(RGDfK).
abstract: The αvβ3-integrin addressing cyclic pentapeptide cyclo(RGDfK) was conjugated to NOPO, 1,4,7-triazacyclononane-1,4-bis[methylene(hydroxymethyl)phosphinic acid]-7-[methylene(2-carboxyethyl)phosphinic acid], a bifunctional chelator with exceptional gallium-68 labeling properties. NOPO-c(RGDfK) and its Ga(III) and Cu(II) complexes showed high affinity to αvβ3 integrin (IC50 = 0.94 ± 0.06, 1.02 ± 0.09, and 0.51 ± 0.06 nM, respectively). (68)Ga labeling of NOPO-c(RGDfK) in an automated GMP-compliant procedure was performed with near-quantitative radiochemical yield, using precursor amounts as low as 0.5 nmol (approximately 0.6 μg). (68)Ga-NOPO-c(RGDfK) was obtained with high purity (>99% by radio-HPLC/TLC) and, optionally, could be produced with specific activities up to 6 TBq/μmol. M21/M21L (human melanoma with high/low αvβ3 integrin expression) xenografted athymic CD-1 nude mice were used for biodistribution, in vivo stability studies, and PET imaging. (68)Ga-NOPO-c(RGDfK) showed rapid and specific uptake in M21 tumor xenografts (2.02 ± 0.34% ID/g at 60 min p.i.) and was found stable in vivo. Its high hydrophilicity is reflected by an octanol-water distribution coefficient (log D = -4.6) which is more than 1 order of magnitude lower compared to respective NOTA or DOTA analogues. As expected, (68)Ga-NOPO-c(RGDfK) thus showed fast renal clearance from nontargeted tissues. We conclude that NOPO might generally prove a useful means to improve renal clearance of corresponding radiopharmaceuticals by increasing the polarity of its bioconjugates. Favorable labeling properties render NOPO conjugates highly recommendable for reliable routine production of (68)Ga-radiopharmaceuticals in a clinical setting.
authors.affiliation: Pharmaceutical Radiochemistry and ‡Institute for Advanced Study and Center of Integrated Protein Science, Technische Universität München , München, Germany.
authors.forename: Jakub
authors.initials: J
authors.lastname: Simeček
authors.forename: Johannes
authors.initials: J
authors.lastname: Notni
authors.forename: Tobias G
authors.initials: TG
authors.lastname: Kapp
authors.forename: Horst
authors.initials: H
authors.lastname: Kessler
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry*; D005710:Gallium Radioisotopes / Q000737:chemistry*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000532:radiotherapy; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry; D010455:Peptides / Q000737:chemistry* / Q000627:therapeutic use; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D002614:Chelating Agents; D005710:Gallium Radioisotopes; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D010455:Peptides; D019275:Radiopharmaceuticals; C047981:arginyl-glycyl-aspartic acid