title: Desferrioxamine as an appropriate chelator for 90Nb: comparison of its complexation properties for M-Df-Octreotide (M = Nb, Fe, Ga, Zr).
abstract: The niobium-90 radioisotope ((90)Nb) holds considerable promise for use in immuno-PET, due to its decay parameters (t½ = 14.6h, positron yield=53%, Eß(+)(mean) = 0.35 MeV and Eß(+)(max) = 1.5 MeV). In particular, (90)Nb appears well suited to detect in vivo the pharmacokinetics of large targeting vectors (50-150 kDa). In order to be useful for immuno-PET chelators are required to both stabilize the radionuclide in terms of coordination chemistry and to facilitate the covalent attachment to the targeting vector. Different chelators were evaluated for this purpose in terms of radiolabelling efficiency and stability of the radiolabelled Nb(V) complex and in order to determine the most suitable candidate for conjugation to a biologically relevant targeting vector. For the purpose of studying the complexation properties the niobium radioisotope (95)Nb was used as an analogue of (90)Nb, by virtue of its longer half-life (35 days) and lower cost (reactor-based production). Acyclic and cyclic chelators were investigated, with desferroxamine [Df: (N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl) (hydroxy)amino]-4-oxobutanoyl} amino)pentyl]-N-hydroxysuccinamide)] emerging as the best candidate. Greater than 99% radiolabelling was achieved at room temperature over a wide pH range. The (95)Nb-Df complex is sufficiently stable for immuno-PET (<7% degradation over 7 days in vitro). As a proof-of-principle, a Df conjugate featuring a well-established targeting vector, (D)-Phe(1)-octreotide, was evaluated. The fast labelling kinetics of the unconjugated chelator (Df) were retained for Df-succinyl-(D)Phe(1)-octreotide (Df-OC), with>90% labelling after 1h at room temperature over the pH range 5-7. Stability studies, performed in vitro in serum at physiological temperature (37 °C), revealed that 87 ± 2% of the radiolabelled molecule remained intact after 7 days. Competition studies with relevant metal ions (zirconium((IV)), gallium((III)) and iron((III))) have been performed with Df-OC to gain insight to the relative stability [Nb-Df]-OC complex to transmetallation. At equimolar metal ion concentrations the [Nb-Df]-OC complex showed the greatest overall stability. The favourable radiolabelling characteristics of Df-OC and its stability indicate that Df is a potentially very useful chelator for the development of radiopharmaceuticals for (90)Nb-PET.
authors.affiliation: Institute of Nuclear Chemistry, Johannes Gutenberg-University Mainz, Fritz-Strassmann-Weg 2, D-55128 Mainz, Germany. Electronic address: varad@lanl.gov.
authors.forename: Valery
authors.initials: V
authors.lastname: Radchenko
authors.affiliation: Institute of Nuclear Chemistry, Johannes Gutenberg-University Mainz, Fritz-Strassmann-Weg 2, D-55128 Mainz, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Busse
authors.affiliation: Institute of Nuclear Chemistry, Johannes Gutenberg-University Mainz, Fritz-Strassmann-Weg 2, D-55128 Mainz, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Roesch
mesh_terms: D002614:Chelating Agents / Q000737:chemistry*; D004355:Drug Stability; D007477:Ions; D007553:Isotope Labeling / Q000379:methods; D008422:Materials Testing; D008670:Metals / Q000737:chemistry*; D009556:Niobium / Q000737:chemistry*; D015282:Octreotide / Q000737:chemistry*; D011829:Radiation Dosage; D011868:Radioisotopes / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*
chemical_list: D002614:Chelating Agents; D007477:Ions; D008670:Metals; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D009556:Niobium; D015282:Octreotide
keywords: Chelators; Desferrioxamine; Df-Octereotide; Positron emitter (90)Nb; Stability