The linear quadridentate N2S2 donor ligand 1,7-bis(N-methylbenzimidazol-2'-yl)-2,6-dithiaheptane (bmdhp) forms mono-and di-hydrate 1 : 1 copper(i1) complexes which are significantly more stable toward autoreduction than those of the non-methylated analogue. The deep green monohydrate of the perchlorate salt crystallises as the mononuclear aqua-complex, [Cu(bmdhp)(OH,)] [CIO4I2, in the monoclinic space group P2,/n, with Z = 4, a = 18.459(3), & = 10.362(2), c = 16.365(3) A, and B = 1 1 7.1 4(1)". The structure was solved and refined by standard Patterson, Fourier, and least-squares techniques to R = 0.047 and R' = 0.075 for 3 343 independent reflections with l > 2 4 4 . The compound consists of [Cu(bmdhp) (OH2)I2+ ions and C104counter ions. The co-ordination around copper is intermediate between trigonal bipyramidal and square pyramidal, with CU-N distances of 1.950(4) and 1.997(4) A, Cu-O(water) 2.225(4) A, and Cu-S 2.328(1) and 2.337(1) A. In the solid state, the perchlorate dihydrate's co-ordination sphere may be a topoisomer of the monohydrate's. A new angular structural parameter, 7 , is defined and proposed as an index of trigonality, as a general descriptor of five-co-ordinate centric molecules. By this criterion, the irregular co-ordination geometry of [Cu(bmdhp)(OH2)I2+ in the solid state is described as being 48% along the pathway of distortion from square pyramidal toward trigonal bipyramidal. In the electronic spectrum of the complex, assignment is made of the S(thioether) -+ Cu charge-transfer bands by comparison with those of the colourless complex Zn(bmdhp)(OH) (C104). E.s.r. and ligand-field spectra show that the copper(ii) compounds adopt a tetragonal structure in donor solvents.Continuing interest in the chemistry of copper-thioether complexes has been promoted by the occurrence of the methionine side-chain as a structurally essential active-site component in a plastocyanin and two a ~u r i n s . ~-~ The additional presence of strongly bound imidazole nitrogen has stimulated the synthesis of various types of copper compounds with biomimetic donors,6-" which are intended to probe the consequences of the nitrogenlsulphur co-ordination and irregular geometry which are the hallmarks of the protein type-1 copper centres.We have prepared a series of chelating ligands with biomimetic donor atoms of the general structure shown below.l2-l5 These quadridentate ligands contain two imidazole nitrogendonor atoms, sterically hindered because they form part of the bulky benzimidazole groups, and two thioether sulphur atoms, with a varying number of carbon atoms

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Technetium-99m labeling of antibodies has been suboptimal because of low affinity adventitious binding, nonspecific labeling, and loss of immunoreactivity. The diamide dithiolate ligand system (N2S2) forms highly stable, well-defined tetradentate complexes with Tc(V). Antibodies and their fragments have been labeled by conjugation of preformed "mTc4,5-bis(thioacetamido)pentanoate active ester to protein amine groups to give a chemically known 99"Tc-N2S2 complex covalently linked to antibody. Evaluations of the "'Tc-N2S2-bound antibodies and their fragments have shown high stability and retained immunoreactivity.Successful targeting ofdiagnostic radionuclides to tumors not only provides a tool to diagnose and stage cancer but also demonstrates feasibility for therapy where ligand systems can be applied to therapy radionuclides. Early studies with radiolabeled antibodies utilized radioiodine (1231/1311) because of extensive experience in protein radioiodination, covalent attachment, and ready availability of the radionuclide (1,2). Improved tumor-to-nontumor ratios were achieved with 1"'In compared to 131I by using diethylenetriaminepentaacetate (DTPA) bifunctional chelating agent technology (3)(4)(5) MATERIALS AND METHODS Preparation of 99mTc-4,5-bis(thioacetamido)pentanoyl (N2S2)-Conjugated Anti-Melanoma 9.2.27 F(ab')2 Fragment. To a mixture of 25 1.l of 4,5-bis(benzoylthioacetamido)pentanoic acid (1.0 mg/ml solution in 90% CH3CN) and 100 ,ul of 1 M NaOH was added 100 mCi of sodium [99mTc]pertechnetate in 1.0 ml of saline (0.9% NaCl). Then 1.0 mg of sodium dithionite (0.10 ml of a freshly prepared 10 mg/ml solution) was added, and the mixture was heated at 750C for 15 min.The pH was brought to about 6 with 0.10 ml of 1 M HCI and 0.30 ml of 0.2 M sodium phosphate buffer (pH 6.0). Then 10.0 mg of 2,3,5,6-tetrafluorophenol (0.10 ml of a 100 mg/ml solution in 90% CH3CN) and 12.5 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.10 ml of a 125.0 mg/ml solution in 90% CH3CN) were added, and the solution was heated at 75°C for 30 min. The resulting tetrafluorophenyl active ester derivative of "mTc-4,5-bis(thioacetamido)pentanoate was purified by loading the reaction mixture on a conditioned C18 cartridge (J. T. Baker), washing with 2.0 ml of 20% (vol/vol) ethyl alcohol/0.01 M sodium phosphate, pH 7.0, eight times, and eluting with 100% CH3CN. The solvent was evaporated under a stream of N2. Then 0.5 ml of the 9.2.27 F(ab')2 fragment (16) at 2.5 mg/ml and 0.50 ml of 0.2 M sodium phosphate (pH 9.0) were added for conjugation. After 15 min at room temperature, 25 mg of lysine (0.25 ml of a 250-mg/ml solution at pH 9.0) was added to quench unreacted ester. The 99mTc-N2S2-9.2.27 F(ab')2 was purified by passage through a G-25 Sephadex column (Pharmacia) equilibrated with phosphate-buffered saline.Abbreviations: N2S2, diamide dithiolate chelating system; 99M Tc-N2S2-9.2.27 F(ab')2, 99mTc-4,5-bis(thioacetamido)pentanoyl-9.2.27 F(ab')2 fragments; DPTA, diethylenetriaminepentaacetate.

Der durch i2 : l‐Kondensation von N‐Methyl‐o‐phenylendiamin und 2,6‐Dithiaheptan‐lJ‐dicarbonsäure in 50proz. Ausb. synthetisierte Titelligand bildet mit Cu(II)‐perchlorat einen Mono‐ und einen Dihydrat‐l :l‐Cu(ll)‐Komplex, die gegen‐ über einer Autoreduktion stabiler sind als jene des nicht‐methylienen Ligand‐ AnalogenDer Monohydtat‐Komplex wird durch eine Röntgenstrukturanalyse als 124 Aquo‐Komplex (I) (RG P21/n, Z=4) mit ionischen Perchlorat‐Ionen identifiziert, der eine Koordination zwischen trigonal‐bipyramidal und quadratisch‐planar besitzt.

Procedures are described for the preparation of various bidentate and linear tetradentate benzimidazoles and benzothiazoles incorporating units such as pyridyl and thioether, and for the preparation of certain thioether dicarboxylic acids precursory to them. Condensations of ortho‐functinal anilines with carboxylic acids were carried out in polyphosphoric acid or refluxing HCl solution. Syntheses are reported for: [HO2C(CH2)2S(CH2)2]2X (X = O, S), 1,9‐bis(benzimidazol‐2‐yl)‐2,5,8‐trithianonane, 1,11‐bis(N‐methylbenzimidazol‐2‐yl)‐3,6,9‐trithiaundecane, 1,11‐bis(2‐benzimidazol‐2‐yl)‐6‐oxo‐3,9‐dithiaundecane, 2‐(2‐pyridyl)benzothiazole, 2,6‐bis(benzothiazol‐2‐yl)pyridine, 2‐(2‐pyridyl)‐N‐methylbenzimidazole, 2‐(2‐pyridylmethyl)benzimidazole and 2‐(N‐methyl‐2‐piperidyl)benzimidazole. The compounds were characterized, where appropriate, by their mass, uv and 1H‐nmr spectra.

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A simplified kiet has been developed for 99mTc protein radiolabeling using an N3S triamide mercaptide bifunctional chelating agent and the preformed chelate approach. The process combined N3S chelating agent, gluconate intermediate transfer agent, stannous reducing agent, and gentisic acid stabilizer into a lyophilized formulation. With sulfur donor atom hemithioacetal protection of the ligand, delta-2,3,5,6-tetrafluorothiophenyl alpha-S-(1-ethoxyethyl)mercaptoacetamido-L-adipoylglycylglycine , optimum 99mTc chelation was achieved in a single step. Subsequent reaction with NR-LU-10 antibody Fab fragment followed by purification via QAE Sephadex anion exchange resin filter afforded 99mTc-N3S-NR-LU-10 Fab conjugate with retained immunoreactivity and effective tumor targeting properties.

Simple and mixed-ligand copper(II) complexes were synthesized and characterized by crystallographic and spectroscopic techniques. The N,S-and O-donor chelating agents used include the following: l,5-bis(benzimidazol-2-yl)-3-thiapentane, BBES; l,5-bis(iV-methylbenzimidazol-2-yl)-3-oxopentane, Me2BBEO; 2,5,8-trimethyl-2,5,8-triazanonane, pmeta; pentane-2,4-dionate anion, acac"; 2,2'-bipyridyl, bpy; 2,2'-biimidazole, biim. The perchlorate of Cu(BBES) crystallizes from methanol as the salt [Cu(BBES)(Me0H)(0H2)](C104)2, with the symmetry of the space group Pi, Z = 2, a = 9.306(3) k,b= 10.072 (5) A, c = 14.194 (5) A, a = 92.23 (2)°, ß = 96.63 (4)°, 7 = 108.56 (3)°, and Pcalcd = 1.66 g-cm"3 456.The structure was solved with the Patterson method, incorporating 3088 of the 3884 independent reflections, to final R values of 5.6% and 6.1% (J?w). The complex cation has a distorted tetragonal pentacoordinate structure ( = 0.27) with the BBES occupying three equatorial positions, with a Cu-S linkage of 2.297 A, and the methanol bound axially. This contrasts with the perchlorate salt of a similar ligand's complex, obtained from ethanol, which has a perchlorate coordinated at this axial position. [Cu(BBES)(acac)]PF6-H20-Et0H was recrystallized from ethyl acetate to give the ester solvate, [Cu(BBES)(acac)]PF6*C4H802. This complex also crystallizes with symmetry Pi, and Z = 2, a = 13.961 (3) A, b = 12.892(3) A,c = 10.154 (3) A, a = 101.57 (4)°, ß = 104.99 (4)°, 7 = 104.34 (4)°, and Pcalcd = 1.160 g-cm"3. The structure was solved by the Patterson method, using 2939 of the 3243 independent reflections, to final R values of 6.3% and 6.1% CRyi). The complex cation is of regularly tetragonal pyramidal geometry ( = 0.02) with an equatorial N202-donor set and the thioether bound axially at 2.696 A, in contrast to the Cu(BBES) perchlorates. There are hydrogen-bonding interactions with benzimidazole and water protons in the lattices of the complexes. ESR spectroscopy shows that the Cu(BBES)2"1" and Cu(Me2BBEO)2+ complexes retain their distorted structures in solution; both give single-line ESR spectra in solution at ambient temperatures. The [Cu(BBES)(acac)]+ salts exhibit pairwise dipolar coupling in their crystalline states. Substitution of ether by thioether as donor causes absorptivity enhancement throughout the visible-near-UV spectrum, and difference spectroscopy has been used to assign sulfur-to-copper charge-transfer transitions. Unlike [Cu(bpy)(acac)]+ and [Cu-(BBES)(acac)]+, the complex cations [Cu(Me2BBEO)(acac)]+ and [Cu(biim)(acac)]+ are unstable toward coordinative disproportionation in the solvents used. The Cu(BBES)2"1" cation in solution is in equilibrium between the/ac-BBES and rwer-BBES isomers, the latter being dominant.