title: A cyclen-based tetraphosphinate chelator for the preparation of radiolabeled tetrameric bioconjugates.
abstract: The cyclen-based tetraphosphinate chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis[methylene(2-carboxyethyl)phosphinic acid] (DOTPI) comprises four additional carboxylic acid moieties for bioconjugation. The thermodynamic stability constants (logK(ML)) of metal complexes, as determined by potentiometry, were 23.11 for Cu(II), 20.0 for Lu(III), 19.6 for Y(III), and 21.0 for Gd(III). DOTPI was functionalized with four cyclo(Arg-Gly-Asp-D-Phe-Lys) (RGD) peptides through polyethylene glycol (PEG4) linkers. The resulting tetrameric conjugate DOTPI(RGD)4 was radiolabeled with (177)Lu and (64)Cu and showed improved labeling efficiency compared with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA). The labeled compounds were fully stable in transchelation challenges against trisodium diethylenetriaminepentaacetate (DTPA) and disodium ethylenediaminetetraacetic acid (ETDA), in phosphate buffered saline (PBS), and human plasma. Integrin αvβ3 affinities of the non-radioactive Lu(III) and Cu(II) complexes of DOTPI(RGD)4 were 18 times higher (both IC50 about 70 picomolar) than that of the c(RGDfK) peptide (IC50 = 1.3 nanomolar). Facile access to tetrameric conjugates and the possibility of radiolabeling with therapeutic and diagnostic radionuclides render DOTPI suitable for application in peptide receptor radionuclide imaging (PRRI) and therapy (PRRT).
authors.affiliation: Lehrstuhl für Pharmazeutische Radiochemie, Technische Universität München, Walther-Meissner Strasse 3, 85748 Garching, Germany.
authors.forename: Jakub
authors.initials: J
authors.lastname: Šimeček
authors.forename: Petr
authors.initials: P
authors.lastname: Hermann
authors.forename: Jana
authors.initials: J
authors.lastname: Havlíčková
authors.forename: Eberhardt
authors.initials: E
authors.lastname: Herdtweck
authors.forename: Tobias G
authors.initials: TG
authors.lastname: Kapp
authors.forename: Nils
authors.initials: N
authors.lastname: Engelbogen
authors.forename: Horst
authors.initials: H
authors.lastname: Kessler
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
authors.forename: Johannes
authors.initials: J
authors.lastname: Notni
mesh_terms: D002614:Chelating Agents / Q000737:chemistry*; D003300:Copper / Q000737:chemistry; D000080027:Cyclams; D005682:Gadolinium / Q000737:chemistry; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D039302:Integrin alphaVbeta3; D008024:Ligands; D008187:Lutetium / Q000737:chemistry; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000737:chemistry*; D013816:Thermodynamics; D015019:Yttrium / Q000737:chemistry
chemical_list: C585429:1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene(2-carboxyethyl)phosphinic acid); D002614:Chelating Agents; D000080027:Cyclams; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D039302:Integrin alphaVbeta3; D008024:Ligands; D010455:Peptides; D010456:Peptides, Cyclic; D010721:Phosphinic Acids; D019275:Radiopharmaceuticals; C099250:cyclic (arginyl-glycyl-aspartyl-phenylalanyl-lysyl); C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D011092:Polyethylene Glycols; D015019:Yttrium; D008187:Lutetium; D003300:Copper; C038072:cyclen; D005682:Gadolinium