title: Cyclam Derivatives with a Bis(phosphinate) or a Phosphinato-Phosphonate Pendant Arm: Ligands for Fast and Efficient Copper(II) Complexation for Nuclear Medical Applications.
abstract: Cyclam derivatives bearing one geminal bis(phosphinic acid), -CH2PO2HCH2PO2H2 (H2L(1)), or phosphinic-phosphonic acid, -CH2PO2HCH2PO3H2 (H3L(2)), pendant arm were synthesized and studied as potential copper(II) chelators for nuclear medical applications. The ligands showed good selectivity for copper(II) over zinc(II) and nickel(II) ions (log KCuL = 25.8 and 27.7 for H2L(1) and H3L(2), respectively). Kinetic study revealed an unusual three-step complex formation mechanism. The initial equilibrium step leads to out-of-cage complexes with Cu(2+) bound by the phosphorus-containing pendant arm. These species quickly rearrange to an in-cage complex with cyclam conformation II, which isomerizes to another in-cage complex with cyclam conformation I. The first in-cage complex is quantitatively formed in seconds (pH ≈5, 25 °C, Cu:L = 1:1, cM ≈ 1 mM). At pH >12, I isomers undergo nitrogen atom inversion, leading to III isomers; the structure of the III-[Cu(HL(2))] complex in the solid state was confirmed by X-ray diffraction analysis. In an alkaline solution, interconversion of the I and III isomers is mutual, leading to the same equilibrium isomeric mixture; such behavior has been observed here for the first time for copper(II) complexes of cyclam derivatives. Quantum-chemical calculations showed small energetic differences between the isomeric complexes of H3L(2) compared with analogous data for isomeric complexes of cyclam derivatives with one or two methylphosphonic acid pendant arm(s). Acid-assisted dissociation proved the kinetic inertness of the complexes. Preliminary radiolabeling of H2L(1) and H3L(2) with (64)Cu was fast and efficient, even at room temperature, giving specific activities of around 70 GBq of (64)Cu per 1 μmol of the ligand (pH 6.2, 10 min, ca. 90 equiv of the ligand). These specific activities were much higher than those of H3nota and H4dota complexes prepared under identical conditions. The rare combination of simple ligand synthesis, very fast copper(II) complex formation, high thermodynamic stability, kinetic inertness, efficient radiolabeling, and expected low bone tissue affinity makes such ligands suitably predisposed to serve as chelators of copper radioisotopes in nuclear medicine.
authors.affiliation: Department of Inorganic Chemistry, Faculty of Science, Charles University in Prague , Hlavova 2030, 12840 Prague, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: David
authors.affiliation: Department of Inorganic Chemistry, Faculty of Science, Charles University in Prague , Hlavova 2030, 12840 Prague, Czech Republic.
authors.forename: Vojtěch
authors.initials: V
authors.lastname: Kubíček
authors.affiliation: Institute of Organic Chemistry and Biochemistry AS CR , Flemingovo náměstí 2, 16610 Prague, Czech Republic.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Gutten
authors.affiliation: Department of Chemistry, Masaryk University , Kotlářská 2, 61137 Brno, Czech Republic.|Central European Institute of Technology (CEITEC), Masaryk University , Kamenice 5, 62500 Brno, Czech Republic.
authors.forename: Přemysl
authors.initials: P
authors.lastname: Lubal
authors.affiliation: Department of Inorganic Chemistry, Faculty of Science, Charles University in Prague , Hlavova 2030, 12840 Prague, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Kotek
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf , Bautzner Landstrasse 400, 01328 Dresden, Germany.
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Pietzsch
authors.affiliation: Institute of Organic Chemistry and Biochemistry AS CR , Flemingovo náměstí 2, 16610 Prague, Czech Republic.
authors.forename: Lubomír
authors.initials: L
authors.lastname: Rulíšek
authors.affiliation: Department of Inorganic Chemistry, Faculty of Science, Charles University in Prague , Hlavova 2030, 12840 Prague, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Hermann
mesh_terms: D003300:Copper / Q000737:chemistry; D007700:Kinetics; D047029:Lactams, Macrocyclic / Q000737:chemistry*; D008024:Ligands; D009683:Nuclear Medicine; D010721:Phosphinic Acids / Q000737:chemistry*; D014961:X-Ray Diffraction
chemical_list: D047029:Lactams, Macrocyclic; D008024:Ligands; D010721:Phosphinic Acids; D003300:Copper