Corinne Bensimon

Evaluation of Bifunctional Chelates for the Development of Gallium-Based Radiopharmaceuticals

Ga radioisotopes, including the generator-produced positron-emitting isotope (68)Ga (t1/2 = 68 min), are of increasing interest for the development of new radiopharmaceuticals. Bifunctional chelates (BFCs) that can be efficiently radiolabeled with Ga to yield complexes with good in vivo stability are needed. To this end, we undertook a systematic comparison of four BFCs containing different chelating moieties: two novel BFCs, p-NO2-Bn-Oxo (1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid) and p-NO2-Bn-PCTA (3,6,9,15-tetraazabicyclo [9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid), and two more commonly used BFCs, p-NO2-Bn-DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and p-NO2-Bn-NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid). Each BFC was compared with respect to radiolabeling conditions, radiochemical yield, stability, and in vivo clearance properties. p-NO2-Bn-PCTA, p-NO2-Bn-Oxo, and p-NO2-Bn-NOTA were all more efficiently radiolabeled with Ga compared to p-NO2-Bn-DOTA. p-NO2-Bn-DOTA required longer reaction time, higher concentrations of BFC, or heating to obtain equivalent radiochemical yields. Better stability was observed for p-NO2-Bn-NOTA and p-NO2-Bn-PCTA compared to p-NO2-Bn-DOTA and p-NO2-Bn-Oxo, especially with respect to transmetalation to transferrin. Ga-radiolabled p-NO2-Bn-Oxo was found to be kinetically labile and therefore unstable in vivo. Ga-radiolabeled p-NO2-Bn-NOTA and p-NO2-Bn-PCTA were relatively inert, while Ga-radiolabeled p-NO2-Bn-DOTA had intermediate stability, losing >20% of Ga in less than one hour when incubated with apo-transferrin. Similar stability differences were seen when incubating at pH 2. In vivo PET imaging and biodistribution studies in mice showed that (68)Ga-radiolabeled p-NO2-Bn-PCTA, p-NO2-Bn-NOTA, and p-NO2-Bn-DOTA all cleared through the kidneys. While there was no statistical difference in the biodistribution results of (68)Ga-radiolabeled p-NO2-Bn-PCTA and p-NO2-Bn-DOTA, (68)Ga-radiolabeled p-NO2-Bn-NOTA cleared more rapidly from blood and muscle tissue but retained at up to 5 times higher activity in the kidneys.

Preparation and characterization of (R2N)2VCl2 [R=Cy, i-Pr] and its activity as olefin polymerization catalyst

Abstract Reaction of VCl3(THF)3 with one equivalent of R2NLi [R=i-Pr, Cy] formed the tetravalent (R2N)2VCl2 [R=i-Pr (1a), Cy (1b)] which was isolated in crystalline form. The formation of these species is likely to be ascribed to a disproportionation reaction since a divalent vanadium complex, VCl2(TMEDA)2 complex was isolated upon treatment of the reaction mixtures with TMEDA. Complexes 1 can be alkylated with RLi to yield the corresponding (R2N)2VR2 (2) derivatives in good yield. Preliminary data on ethylene–propylene (EP) co-polymerization obtained with compounds 1 in conjunction with various aluminum alkyl compounds are described.

Ligand steric bulk: A neglected factor in the formation of CrCr supershort contacts

Abstract The ability of three center chelating ligands to form dichromium units and to enforce short and very short CrCr contacts is examined in a consistent series of cyclohexyl amidinate chromium complexes, with the aim of understanding the factors intrinsic in the nature of the bridging ligands which are able to promote or disfavor dinuclear aggregation and to determine the extent of intermetallic separation. The present study describing the crystal structures of the dinuclear [(CyNC(H)NCy)2Cr]2·C7H8 (1) and mononuclear (CyNC(CH3)NCy)2Cr (2), {CyNC[Ph(o-CH2NMe2)]NCy}2Cr·2THF (3) and [(Me3Si)NC(Ph)N(SiMe3)]2Cr (4) indicates that the steric interaction between the lateral cyclohexyl and the central amidinate group is capable of determining the nuclearity (monomeric versus dimeric) and probably the extent of intermetallic separation. Crystal data are as follows. 1: C52H84N8Cr2·toluene, M=1017.41, monoclinic, P21/c, a=13.682(5), b=17.446(3), c=24.521(3) A, β=90.02(5)°, V=5853(3) A3, Z=4, T=−30 °C, Mo Kα, R=0.104, Rw=0.077 for 4030 reflections out of 10319 unique; 2: C28H50N4Cr, M=494.73, orthorhombic, Pnma, a=8.104(1), b=26.572(4), c=12.533(2) A, V=2699(1) A3, Z=4, T=−157 °C, Mo Kα, R=0.054, Rw=0.069 for 1580 reflections out of 2752 unique; 3: C44H68N6Cr·2THF, M=853.16, triclinic, P 1 , a=12.293(5), b=20.437(5), c=11.071(4) A, α=94.55(3), β=111.72(3), γ=73.86(3)°, V=2481(1) A3, Z=2, T=−157 °C, Mo Kα, R=0.093, Rw=0.081 for 6492 reflections out of 8710 unique.

Isolation and characterization of 4-acetyl-benzoxazolin-2-one (4-ABOA), a new benzoxazolinone from Zea mays

Abstract The previously unreported 4-acetyl-benzoxazolin-2-one (4-ABOA, 1 ) was isolated from corn kernels. Its structure was determined by MS, NMR and X-Ray crystallography.

Preparation, structure and properties of triphenylphosphine rhodium aryloxides

Abstract The reaction of Wilkinsons catalyst with NaOAr in toluene cleanly affords the corresponding aryloxide complexes Rh(PPh3)3OAr (1). In solution, 1 exists in equilibrium with PPh3 and the corresponding Rh(PPh3)2(π-ArO) (2). The addition of HOAr shifts the equilibrium completely toward the corresponding adducts 2·2HOAr, due to hydrogen bonding between the oxygen atom of the π-coordinated OAr ligand and two molecules of HOAr. Heating of 1a-d in toluene at 60–80°C leads to the elimination of HOAr with concomitant cyclometallation of a phenyl ring of one PPh3 ligand, affording mixtures of 1,2·2HOAr, a cyclometallated Rh complex and PPh3. At room temperature, a reverse reaction slowly occurs to give equilibrium mixtures of 1, 2 and PPh3. Complexes 1 readily with water, CO and H2, affording Rh2(PPh3)4(μ-OH)2, Rh(PPh3)2(CO)OAr (3) and HRh(PPh3)3, respectively. The latter complex was also obtained when complexes 1 were treated with methanol. The structures of the phenoxide complexes 1 and 2·2PhOH and of p-nitrophenoxide complex 3 were established by X-ray diffraction.

Reactivity of a (FeNO)-(FeNO3) system in the presence of a ferrocene-ferricinium group tethered nearby via a ferrocenyl phosphine linkage (FcP2) : crystal structures of [{Fe(NO)2Cl}2(μ-FcP2)] and [Fe(NO)2(FcP2)]

Abstract The nitrosyl dimer [{Fe(NO) 2 (Cl) 2 }] ( 1 ) reacts with 1,1′-bis(diphenylphosphino)ferrocene (FcP 2 ) to yield [Fe(NO) 2 (Cl)] 2 (μ-FcP 2 ) ( 2 ), the structure of which has been determined. The FcP 2 moiety bridges two Fe(NO) 2 (Cl) groups symmetrically. Oxygenation of 1 in the presence of FcP 2 yields [Fe(NO 3 ) 2 Cl(O 2 P 2 Fc)] ( 5 ): complex 5 catalyses the autoxidation of cyclohexene. It transfers the oxygen atoms of its nitrato groups to phosphines. When allowed to react with an excess of FcP 2 , 2 gives [Fe(NO) 2 (Fcp 2 )] ( 4 ); the subsequent formation of [Fe(NO)Cl 2 (FcP 2 O)] ( 3 ) is attributed to the reaction of 4 with chlorine liberated in situ. The structure of 4 was also determined.

Flow-Dependent Uptake of 123I-CMICE-013, a Novel SPECT Perfusion Agent, Compared with Standard Tracers

Rotenone derivatives have shown promise in myocardial perfusion imaging (MPI). CMICE-013 is a novel 123I-labeled rotenone derivative developed for SPECT MPI. The objective of this study was to assess the image quality of CMICE-013 and compare its uptake with tetrofosmin, sestamibi, and 201Tl in vivo in a porcine model of stress-induced myocardial ischemia. Methods: Microspheres were injected simultaneously with the radiotracer injections at rest and stress to measure blood flow. Mimicking a 1-d tetrofosmin protocol, stress imaging used 3 times as much activity and occurred 1 h after the rest injection. SPECT images were obtained at both rest and stress. After imaging, the heart was sectioned into 44–50 pieces. In each heart sample, the tracer uptake was measured in a γ counter. The images were aligned, and the decay-corrected ratio of the signals at rest and stress was used to separate the well-counter signal into rest and stress components. The uptake at rest and stress was compared with microsphere flow measurements. Results: The CMICE-013 images showed good contrast between the heart and surrounding organs, with heart-to-liver and heart-to-lung uptake ratios similar to those of the standard tracers. Uptake of CMICE-013 was 1.5% of the injected dose at rest and increased more rapidly with increased blood flow than did the standard SPECT tracers. The percentage injected dose of CMICE-013 taken up by the heart was greater (P < 0.05) than 201Tl, tetrofosmin, or sestamibi at flows greater than 1.5 mL/min/g. Conclusion: CMICE-013 is a promising new SPECT MPI agent.

Pharmacokinetic modulation of radiolabeled chelates facilitated by phosphonate ester coordinating groups.

Chelates are an important part of metal based radiopharmaceuticals. This study examines the possible application of phosphonate ester moieties incorporated into chelates, where the ester group can be changed to modulate the pharmacokinetics of the radiopharmaceutical, while the phosphonate stably binds the metal radioisotope. Two phosphonate ester containing chelates, PCTMB and PCTM(F)E, were compared to the carboxylate containing analogue, p-Bn-PCTA, with respect to radiochemistry with several radionuclides (In-111, Ga-68, Ga-67, Cu-64). The phosphonate ester derivatives were similar to p-Bn-PCTA with respect to efficient radiolabeling with each of the radiometals under mild, aqueous conditions. Each of the radiolabeled phosphonate esters was also shown to be stable under physiological conditions in vitro. The phosphonate ester moieties did exhibit a propensity to degrade under more acidic conditions. Biodistribution studies in mice with the In-111 radiolabeled versions of PCTMB, PCTM(F)E and p-Bn-PCTA demonstrated the ability of the phosphonate ester functionalities to change the pharmacokinetics of the BFCs. With increasing lipophilicity, the phosphonate ester derivatives showed increasing hepatic clearance; but no significant increase in background tissue uptake (bone, muscle) was observed, and all the In-111 radiolabeled BFCs were substantially cleared within 24 h. The substitution of phosphonate ester for carboxylate functional groups in chelates may be an effective strategy to assist in optimizing the pharmacokinetics of radiopharmaceuticals through varying of the ester group.