Edward H. Wong

Copper Chelation Chemistry and its Role in Copper Radiopharmaceuticals

Molecular imaging is an important scientific discipline that plays a major role in clinical medicine and pharmaceutical development. While several imaging modalities including X-ray computed tomography (CT) and magnetic resonance imaging (MRI) generate high-resolution anatomical images, positron emission tomography (PET) and single photon emission computed tomography (SPECT) offer insight into the physiological processes that occur within a living organism. Of these two nuclear medicine imaging techniques, PET has advantages with respect to sensitivity and resolution, and this has led to the production and development of many positron emitting radionuclides that include non-traditional radionuclides of the transition metals. Copper-64 (t(1/2) = 12.7 h, beta(+): 17.4%, E(beta+max) = 656 keV; beta(-): 39%, E(beta-max) = 573 keV) has emerged as an important positron emitting radionuclide that has the potential for use in diagnostic imaging and radiotherapy. However, (64)Cu must be delivered to the living system as a stable complex that is attached to a biological targeting molecule for effective imaging and therapy. Therefore, significant research has been devoted to the development of ligands that can stably chelate (64)Cu. This review discusses the necessary characteristics of an effective (64)Cu chelator, while highlighting the development and evaluation of (64)Cu-complexes attached to biologically-targeted ligands.

Preparation and Biological Evaluation of Copper-64–Labeled Tyr3-Octreotate Using a Cross-Bridged Macrocyclic Chelator

Purpose: Somatostatin receptors (SSTr) are expressed on many neuroendocrine tumors, and several radiotracers have been developed for imaging these types of tumors. For this reason, peptide analogues of somatostatin have been well characterized. Copper-64 (t1/2 = 12.7 hours), a positron emitter suitable for positron emission tomography (PET) imaging, was shown recently to have improved in vivo clearance properties when chelated by the cross-bridged tetraazamacrocycle 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo(6.6.2)hexadecane (CB-TE2A) compared with 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA). Experimental Design: CB-TE2A and TETA were conjugated to the somatostatin analogue tyrosine-3-octreotate (Y3-TATE) for evaluation of CB-TE2A as a bifunctional chelator of 64Cu. The in vitro affinity of each compound for SSTr was determined using a homologous competitive binding assay. In vivo characteristics of both radiolabeled compounds were examined in biodistribution and microPET studies of AR42J tumor-bearing rats. Results: Cu-CB-TE2A-Y3-TATE (Kd = 1.7 nmol/L) and Cu-TETA-Y3-TATE (Kd = 0.7 nmol/L) showed similar affinities for AR42J derived SSTr. In biodistribution studies, nonspecific uptake in blood and liver was lower for 64Cu-CB-TE2A-Y3-TATE. Differences increased with time such that, at 4 hours, blood uptake was 4.3-fold higher and liver uptake was 2.4-fold higher for 64Cu-TETA-Y3-TATE than for 64Cu-CB-TE2A-Y3-TATE. In addition, 4.4-times greater tumor uptake was detected with 64Cu-CB-TE2A-Y3-TATE than with 64Cu-TETA-Y3-TATE at 4 hours postinjection. MicroPET imaging yielded similar results. Conclusions: CB-TE2A appears to be a superior in vivo bifunctional chelator of 64Cu for use in molecular imaging by PET or targeted radiotherapy due to both improved nontarget organ clearance and higher target organ uptake of 64Cu-CB-TE2A-Y3-TATE compared with 64Cu-TETA-Y3-TATE.

Exploiting Incommensurate Symmetry Numbers: Rational Design and Assembly of M2M3′L6 Supramolecular Clusters with C3h Symmetry

Mixed-metal mesocates [M2 Pd3 Br6 L6 ]4- (M=TiIV , SnIV ; L=4-diphenylphosphanyl-catecholate) have been synthesized, in which the two incommensurate symmetry elements generated by the different metal ions are linked by a rigid, bifunctional ligand to generate a C3h -symmetrical cluster (see picture).

Two novel zinc(II) complexes of the 1,8-cross-bridged cyclam ligand and their structures

Abstract Without special precautions to exclude moisture or protic solvents, cross-bridged cyclam ligand 1 was found to readily complex zinc dichloride and yield two types of cis-folded complexes in the solid-state; one a chloride-bridged dimer and the other an aqua complex featuring a coordinated [ZnCl4]2− counterion.

Chelating and monodentate coordination modes of the tetraphenyldiphosphoxane (Ph2POPPh2) ligand

Abstract The crystal and molecular structures of the Cr and Mo complexes cis-(CO)4 M(PPh 2 OP Ph2) have been determined. Mo complex: C28H20O5P2Mo, triclinic, P 1 , a 10.016(2), b 11.419(3), c 13.237(3) A, α 106.18(2), β 95.78(2), γ 112.78(2)°, Z = 2, Dcalc = 1.515 Mg m−3. The final residual is RF = 0.027 for 3718 observed reflections at 23°C. Cr complex: C28H20O5P2Cr, triclinic, P 1 , a 9.887(1), b 11.438(2), c 13.020(2) A, α 106.43(1), β 95.05(1), γ 112.59(1)°, Z = 2, Dcalc 1.438 Mg m−3. The final residual is RF = 0.043 for 2817 observed reflections at 23°C. The two structures are isomorphous with approximate octahedral coordination geometry around each metal and feature the tetraphenyldiphosphoxane Ph2POPPh2 ligand in a chelating mode. Hydrolysis of the Cr, Mo, and W chelate complexes under basic conditions yielded the cis-(CO)4M(PPh2O)2H− species which can be reconverted to the parent cis-(CO)4 M(PPh 2 OP Ph2) by acidification and dehydration using trifluoroacetic acid in trifluoroacetic anhydride. A monodentate coordination mode of the Ph2POPPh2 ligand was identified in the complex (CO)5MoPPh2OPPh2 prepared from the reaction of CIPPh2 with (CO)5MoPPh2O−. This monodentate ligand becomes chelating upon warming of the complex in solution.

Isomeric Trimethylene and Ethylene Pendant-armed Cross-bridged Tetraazamacrocycles and in Vitro/in Vivo Comparisions of their Copper(II) Complexes

Ethylene cross-bridged tetraamine macrocycles are useful chelators in coordination, catalytic, medicinal, and radiopharmaceutical chemistry. Springborg and co-workers developed trimethylene cross-bridged analogues, although their pendant-armed derivatives received little attention. We report here the synthesis of a bis-carboxymethyl pendant-armed cyclen with a trimethylene cross-bridge (C3B-DO2A) and its isomeric ethylene-cross-bridged homocyclen ligand (CB-TR2A) as well as their copper(II) complexes. The in vitro and in vivo properties of these complexes are compared with respect to their potential application as 64Cu-radiopharmaceuticals in positron emission tomography (PET imaging). The inertness of Cu-C3B-DO2A to decomplexation is remarkable, exceeding that of Cu-CB-TE2A. Electrochemical reduction of Cu-CB-TR2A is quasi-reversible, whereas that of Cu-C3B-DO2A is irreversible. The reaction conditions for preparing 64Cu-C3B-DO2A (microwaving at high temperature) are relatively harsh compared to 64Cu-CB-TR2A (basic ethanol). The in vivo behavior of the 64Cu complexes was evaluated in normal rats. Rapid and continual clearance of 64Cu-CB-TR2A through the blood, liver, and kidneys suggests relatively good in vivo stability, albeit inferior to 64Cu-CB-TE2A. Although 64Cu-C3B-DO2A clears continually, the initial uptake is high and only about half is excreted within 22 h, suggesting poor stability and transchelation of 64Cu to proteins in the blood and/or liver. These data suggest that in vitro inertness of a chelator complex may not always be a good indicator of in vivo stability.

Assemblage of multimetal complexes using the diphosphoxane (POP) linkage

Abstract Heterobimetallic complexes can be prepared using the monodentate diphosphoxane ligand in Mo(CO)5PPh2OPPh2. Reactions with Cr(CO)5CH3CN and Fe2(CO)9 yielded the corresponding bimetallic products. The structure of Mo(CO)5PPh2OPPh2Fe(CO)4 was established by a single-crystal X-ray study. Cell data: Space group P 1 , monoclinic, a 10.533(2), b 10.993(2), c 16.439(3) A; α 97.86(2), β 92.34(1), γ 116.20(1)°; Z = 2, Dc 1.561 g cm−3 RF is 0.037 for 3830 observed reflections. The diphosphoxane ligand was found to bridge an octahedral Mo and the axial site of a trigonal bipyramidal Fe. Reaction of two equivalents of Mo(CO)5PPh2OPPh2 with (PhCN)2PdCl2 produced the trimetallic complex trans-PdCl2[PPh2OPPh2Mo(CO)5]2. The trimetallic complexes P[OPR2Mo(CO)5]3 were prepared from the reaction of PCl3 with Na[OPR2Mo(CO)5] (R = Ph, OEt). Similarly, a bimetallic complex PhP[OP(OEt)2Mo(CO)5]2 can be prepared from PhPCl2. These products illustrate the usefulness of the diphosphoxane linkage in the synthesis of multimetal complexes.

NMR Spectral Studies of Interactions Between the Accelerants SPS and MPS and Copper Chlorides

Proton and C-13 NMR spectroscopic studies of possible interactions of the copper electroplating accelerant disodium bis(3-sulfopropyl)disulfide (SPS) and its reduced form sodium 3-mercaptopropylsulfonate (MPS) with both cuprous chloride and cupric chloride were carried out in 0.25 M D 2 SO 4 /D 2 O with reagent concentrations between millimolar and 0.1 M under anaerobic conditions. It was confirmed that MPS reacted with CuCl to yield Cu(I)―thiolate products. No evidence for formation of a solution Cu(I)―SPS complex from CuCl and SPS was found. Instead, a redox reaction yielded a Cu(I)―thiolate along with Cu(II) with an estimated equilibrium constant of 5.2 × 10 ―3 M ―1 . The previously reported reaction of aqueous cupric chloride with MPS was investigated further under anaerobic conditions. In addition to SPS, Cu(I)―thiolate products similar to those from the CuCl/MPS reaction were identified. The reaction was found to be complete only upon addition of over 2 equiv of MPS. No evidence for any interaction between CuCl 2 and SPS was observed.

Coordinated tautomers of a bis-(phosphoryl)-phosphine: assemblage of group VIB metal complexes containing diphosphoxane (POP) linkages

Abstract Reactions of the hydrogen-bridged chelates cis-(CO)4M(PPh2O-)2H− (M  Cr, Mo, W) with Cl2PPh yield complexes of the type cis-(CO)4 M(-P Ph2-P(O)Ph-O-PPh2) containing five-membered chelate rings. X-ray structural determination of the Mo complex confirmed the formation of the heterocycle. Crystal data: space group C2/c; a 16.477(3), b 19.845(3), c 20.512(4) A; β 106.61(2)°; Z = 8, Dcalc 1.421 Mg m−3. The final residual is 0.027 for 4737 observed reflections. The five-membered chelate ring is nonplanar with the phosphoryl P 0.888(2) A out of an approximate plane containing the other four atoms. For the tungsten analogue, 31P NMR data are consistent with the initial formation of a six-membered heterocyclic intermediate: cis-(CO)4W(PPh2-O)2PPh, which tautomerizes readily to give the final product. Six-membered chelate rings containing the (PPh2O)2PPh ligand can be assembled by the reaction of cis-(CO)4Mo(PPh2Cl)2 with (CO)5M-PPhO2H− (M = Cr, Mo). Complexes of the type cis-(CO)4Mo(PPh2O-)2PPh-M(CO)5 (M = Cr, Mo) were isolated. Reaction of Cl2PPh with two equivalents of (CO)5Mo-PPh2O− yields PhP(-OPPh2-Mo(CO)5)2. The above complexes represent coordination-stabilized PhP(-OPPh2)2 and (Ph2P-)-

High-resolution solid-state 11B and 13C MAS NMR of icosahedral carboranes

Abstract The globular-shaped icosahedral carboranes, o -, m -, and p -C 2 B 10 H 12 , yield high-resolution 11 B and 13 C MAS solid-state NMR spectra. Chemical shifts and linewidths are comparable to those of solution spectra. Spin—lattice relaxation times indicate the quadrupolar mechanism to be dominant for the B-11 relaxation. Linewidths of spectra recorded at 96 MHz and 64 MHz were similar. At 298 K, the 13 C T 1 of p -carborane was found to be an order of magnitude smaller than those of the other two isomers. This can be attributed to the higher phase transition temperature of p -carborane indicative of the stronger intermolecular dipolar CH interactions made possible by the para -carbon vertices. Substitution on o -carborane by a methyl group yields spectra of comparable linewidths to those of the parent compound. Substitution by a bulkier phenyl group, however, results in extensive broadening of both 11 B and 13 C signals of the derivative 1-Ph- o -C 2 B 10 H 11 .