Sylvie Pailloux

Di-macrocyclic terephthalamide ligands as chelators for the PET radionuclide zirconium-89

The development of bifunctional chelators (BFCs) which can stably chelate zirconium-89 ((89)Zr) while being conjugated to targeting molecules is an area of active research. Herein we report the first octadentate terephthalamide ligands, which are easily radiolabeled with (89)Zr and are highly stable in vitro. They represent a novel class of chelators, which are worthy of further development as BFCs for (89)Zr.

Synthesis and lanthanide coordination chemistry of trifluoromethyl derivatives of phosphinoylmethyl pyridine N-oxides.

A synthetic route for the formation of 2-[bis(2-trifluoromethylphenyl)phosphinoylmethyl]pyridine N-oxide (1c) and 2-[bis(3,5-trifluoromethylphenyl)phosphinoylmethyl]pyridine N-oxide (1d) was developed and the new ligands characterized by spectroscopic methods and single-crystal X-ray diffraction analyses. The coordination chemistry of 1c was examined with Yb(NO3)3 and the molecular structure of one complex, [Yb(1c)(NO3)3(DMF)].DMF.0.5H2O, was determined by single-crystal X-ray diffraction methods. The ligand is found to coordinate in a bidentate fashion, and this is compared against lanthanide coordination chemistry observed for the related ligand, [Ph2P(O)CH2] C5H4NO.

Evaluation of a 3-hydroxypyridin-2-one (2,3-HOPO) Based Macrocyclic Chelator for 89Zr4+ and Its Use for ImmunoPET Imaging of HER2 Positive Model of Ovarian Carcinoma in Mice

A novel octadentate 3-hydroxypyridin-2-one (2,3-HOPO) based di-macrocyclic ligand was evaluated for chelation of 89Zr; subsequently, it was used as a bi-functional chelator for preparation of 89Zr-labeled antibodies. Quantitative chelation of 89Zr4+ with the octadentate ligand forming 89ZrL complex was achieved under mild conditions within 15 minutes. The 89Zr-complex was stable in vitro in presence of DTPA, but a slow degradation was observed in serum. In vivo, the hydrophilic 89Zr-complex showed prevalently renal excretion; and an elevated bone uptake of radioactivity suggested a partial release of 89Zr4+ from the complex. The 2,3-HOPO based ligand was conjugated to the monoclonal antibodies, HER2-specific trastuzumab and an isotypic anti-gD antibody, using a p-phenylene bis-isothiocyanate linker to yield products with an average loading of less than 2 chelates per antibody. Conjugated antibodies were labeled with 89Zr under mild conditions providing the PET tracers in 60-69% yield. Despite the limited stability in mouse serum; the PET tracers performed very well in vivo. The PET imaging in mouse model of HER2 positive ovarian carcinoma showed tumor uptake of 89Zr-trastuzumab (29.2 ± 12.9 %ID/g) indistinguishable (p = 0.488) from the uptake of positive control 89Zr-DFO-trastuzumab (26.1 ± 3.3 %ID/g). In conclusion, the newly developed 3-hydroxypyridin-2-one based di-macrocyclic chelator provides a viable alternative to DFO-based heterobifunctional ligands for preparation of 89Zr-labeled monoclonal antibodies for immunoPET studies.

Radiolytic Degradation in Lanthanide/Actinide Separation Ligands–NOPOPO: Radical Kinetics and Efficiencies Determinations

Abstract Trivalent lanthanide/actinide separations from used nuclear fuel occurs in the presence radiation fields that degrades the extraction ligands and solvents. Here we have investigated the stability of a new ligand for lanthanide/actinide separation; 2,6-bis[(di(2-ethylhexyl)phosphino)methyl] pyridine N,P,P-trioxide, TEH(NOPOPO). The impact of γ-radiolysis on the distribution ratios for actinide (Am) and Lanthanide (Eu) extraction both in the presence and absence of an acidic aqueous phase by TEH(NOPOPO) was determined. Corresponding reaction rate constants for the two major radicals, hydroxyl and nitrate, were determined for TEH(NOPOPO) in the aqueous phase, with room temperature values of (3.49 ± 0.10) × 109 and (1.95 ± 0.15) × 108 M–1 s–1, respectively. The activation energy for this reaction was found to be 30.2 ± 4.1 kJ mol–1. Rate constants for two analogues (2-methylphosphonic acid pyridine N,P-dioxide and 2,6-bis(methylphosphonic acid) pyridine N,P,P-trioxide) were also determined to assist in determining the major reaction pathways.

Synthesis and reactivity of (benzoxazol-2-ylmethyl)phosphonic acid.

An efficient three step synthesis of (benzoxazol-2-ylmethyl)phosphonic acid (6-H(2)) is described along with IR, mass spectrometry (MS), and (1)H, (13)C, and (31)P NMR spectroscopic characterization data, and a single crystal X-ray diffraction structure determination. 6-H(2) is unstable in acidic aqueous solutions (pH < 4) undergoing ring-opening to give [(2-hydroxyphenylcarbamoyl)methyl] phosphonic acid (7-H(2)) that is characterized by IR, MS, and NMR methods. The protonation constants (pK(a)) for 7-H(2) have been measured, and crystal structure determinations for (NH(4))(7-H) and K(7-H)·DMF are described. Reactions of NaOH and KOH with 6-H(2) in MeOH/H(2)O solutions led to isolation and crystal structure determinations of the salts [Na(6-H)·H(2)O](2), K(6-H), Na(3)(6)(6-H)·H(2)O, and [K(2)(6)](2)·3H(2)O. The complexation reactions of 7-H(2) with La(III), Nd(III), and Gd(III), as a function of pH, were also examined by titrametric methods, and a model for the 1:1 anion binding with Ln(III) cations is proposed.

Direct synthesis of trifluoromethyl decorated diphenylphosphites. Unusual non-bonded structural features in bis-[(2-trifluoromethyl)phenylphosphite: [2-(CF3)C6H4]2P(O)H]

A direct, Grignard reagent-based route for the syntheses of [2-(CF3)C6H4]2P(O)H (1) and [3,5-(CF3)2C6H3]2P(O)H (2) has been developed and the isolation and characterization of these crystalline reagents is described. The crystal structures for 1 and 2 were determined and the structure of 1 reveals unexpected close non-bonded interaction between F-atoms of one CF3 group and the back-side of the central phosphorus atom.

Synthesis of 2,5-bis(phosphinoylmethyl)- and 2,5-bis(thiophosphinoylmethyl)-thiophenes

The 2,5-bis(phosphinoylmethyl)-thiophenes ((Oct)(EtO)P(O)CH2)2C4H2S and ((Ph)(EtO)P(O)CH2)2C4H2S are obtained from the appropriate phosphites, RP(OEt)2 (R=Oct, Ph) and (BrCH2)2C4H2S by using Arbusov reaction conditions. The analog ((Oct)2P(O)CH2)2C4H2S is more conveniently obtained via the reaction of the phosphono-Grignard reagent (Oct)2P(O)MgBr and (BrCH2)2C4H2S. An improved alternate Arbusov synthesis of the known (Ph2P(O)CH2)2C4H2S is described along with its conversion to (Ph2P(S)CH2)2C4H2S via Lawesson chemistry. The new compounds are characterized by MS, IR and NMR methods, and the molecular structures of (Ph2P(O)CH2)2C4H2S and (Ph2P(S)CH2)2C4H2S have been confirmed by single crystal X-ray diffraction methods.

CCDC 977955: Experimental Crystal Structure Determination

Related Article: Sabrina Ouizem, Sylvie L. Pailloux, Alisha D. Ray, Eileen N. Duesler, Diane A. Dickie, Robert T. Paine, Benjamin P. Hay|2014|Eur.J.Org.Chem.||3132|doi:10.1002/ejoc.201400120