title: Pyclen Tri-n-butylphosphonate Ester as Potential Chelator for Targeted Radiotherapy: From Yttrium(III) Complexation to (90)Y Radiolabeling.
abstract: The Y(3+) complex of PCTMB, the tri-n-butyl phosphonate ester of pyclen (3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene), was synthesized as well as its Ho(3+) and Lu(3+) analogues. X-ray diffraction analyses revealed isomorphous dimeric M2(PCTMB)2·9H2O (M = Y, Ho, Lu) structures that crystallize in the centrosymmetric P1̅ triclinic space group. (1)H NMR and UV studies in aqueous solutions indicated that Y(3+) complexation is fast, being quantitative in 167 min at pH 3.8 and in 13 min at pH 5.5 (25 °C, acetate buffer, I = 0.150 M, [Y(3+)] = [PCTMB] = 0.2 mM). (1)H NMR DOSY and photon correlation spectroscopy experiments evidenced the formation of aggregates in chloroform with a bimodal distribution that changes slightly with concentration (11-24 and 240-258 nm). The behavior of the acid-assisted dissociation of the complex of Y(3+) with PCTMB was studied under pseudo-first-order conditions, and the half-life of the [Y(PCTMB)] complex in 0.5 M HCl at 25 °C was found to be 37 min, a value that decreases to 2.6 min in 5 M HCl. The Y(3+) complex of PCTMB is thermodynamically very stable, with a stability constant of log KY-PCTMB = 19.49 and pY = 16.7 measured by potentiometry. (90)Y complexation studies revealed fast radiolabeling kinetics; optimal radiolabeling conditions were obtained for (90)Y in acetate medium, PCTMB at 10(-4) to 10(-2) M in acetate buffer pH = 4.75, 15 min at 45-60 °C. In vitro stability studies in human serum showed that [(90)Y(PCTMB)] is quite stable, with about 90% of the activity still in the form of the radiotracer at 24 h and 80% from 48 h to 72 h. A comparison with other ligands such as PCTA, DOTA, and DTPA already used for in vivo application shows that [(90)Y(PCTMB)] is an interesting lipophilic and neutral analogue of these reference chelates for therapeutic applications in aqueous and nonaqueous media.
authors.affiliation: Université de Bretagne Occidentale, UMR-CNRS 6521, UFR des Sciences et Techniques , 6 Avenue Victor le Gorgeu, CS 93837, 29238 Brest Cedex 3, France.
authors.forename: Mariane
authors.initials: M
authors.lastname: Le Fur
authors.affiliation: Université de Bretagne Occidentale, UMR-CNRS 6521, UFR des Sciences et Techniques , 6 Avenue Victor le Gorgeu, CS 93837, 29238 Brest Cedex 3, France.
authors.forename: Maryline
authors.initials: M
authors.lastname: Beyler
authors.affiliation: Département de Médecine Nucléaire, Centre Eugène Marquis, INSERM U991 , Avenue de la Bataille Flandres-Dunkerque, CS 44229, 35042 Rennes Cedex, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lepareur
authors.affiliation: Guerbet Group, Centre de Recherche d'Aulnay-sous-Bois , BP 57400, 95943 Roissy CdG Cedex, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Fougère
authors.affiliation: Centro de Investigaciones Científicas Avanzadas (CICA) and Departamento de Química Fundamental, Universidade da Coruña , Campus da Zapateira-Rúa da Fraga 10, 15008 A Coruña, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Platas-Iglesias
authors.affiliation: Guerbet Group, Centre de Recherche d'Aulnay-sous-Bois , BP 57400, 95943 Roissy CdG Cedex, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rousseaux
authors.affiliation: Université de Bretagne Occidentale, UMR-CNRS 6521, UFR des Sciences et Techniques , 6 Avenue Victor le Gorgeu, CS 93837, 29238 Brest Cedex 3, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Tripier
mesh_terms: D053961:Azabicyclo Compounds / Q000737:chemistry; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D004355:Drug Stability; D006801:Humans; D007553:Isotope Labeling; D009682:Magnetic Resonance Spectroscopy; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry*; D011878:Radiotherapy / Q000379:methods*; D044967:Serum; D013056:Spectrophotometry, Ultraviolet; D013816:Thermodynamics; D015019:Yttrium / Q000737:chemistry*; D015021:Yttrium Radioisotopes / Q000737:chemistry
chemical_list: D053961:Azabicyclo Compounds; D002614:Chelating Agents; D063065:Organophosphonates; D019275:Radiopharmaceuticals; D015021:Yttrium Radioisotopes; C582723:pyclen; D015019:Yttrium