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- Rhenium (4)
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Two new octahedral cluster complexes [Re6S8(3,5-Me2PzH)6]Br2 · 2(3,5-Me2PzH) (1) and [Re6Se8(3,5-Me2PzH)6]Br2 · 2(3,5-Me2PzH) (2), where 3,5-Me2PzH is 3,5-dimethylpyrazole, have been synthesized using reaction of rhenium chalcobromide complexes Cs4[Re6S8Br6] · 2H2O and Cs3[Re6Se8Br6] · H2O, respectively, with molten 3,5-dimethylpyrazole. Both compounds synthesized were characterized by X-ray single-crystal diffraction and chemical analysis, IR and luminescent spectra.
Technetium- and Rhenium-Labelled Fatty Acids as Model Compounds for Myocardial Metabolism Imaging
(2002)
In an attempt to develop new technetium-based radiopharmaceuticals for the non-invasive diagnosis of oxidative myocardial metabolism, rhenium model compounds according to the 3+1' mixed ligand approach as well as the organometallic tricarbonyl-design were synthesized. The geometrical impact of different chelates on the integrity of the fatty acid head structure was determined by single crystal X-ray analyses. To evaluate the diagnostic potential of the analogous Technetium-99m compounds, fatty acid complexes of the 3+1' mixed ligand type were prepared on n.c.a.-level and studied in the isolated constant-flow-perfused guinea pig heart model; compared to established [123I]Iodine-labelled fatty acid radiotracers, the tested Technetium-99m derivatives showed a specific, however significantly lower myocardial extraction rate.
This work is part of an effort to develop chelating agents for stable binding and easy conjugation of Re-188 to biologically interesting structures. Starting from the well-known in vivo stability of [188ReO(DMSA)2]-, we want to exploit this coordination system for the design of 188ReO(V) chelates, which are stable toward reoxidation to perrhenate and toward ligand exchange under all conditions of radiopharmaceutical development. Therefore, a new type of tetradentate ligand has been synthesized by bridging two molecules of N,N'-diisobutyl-2,3-dimercaptosuccinamide with N-(3-aminopropyl)propane-1,3-diamine. The resulting stereoisomeric tetrathiolato S4 ligand of composition (iBu)2N(O)C-C(SH)-C(SH)-C(O)NH-(CH2)3-NH-(CH2)3-NHC(O)-C(SH)-C(SH)-C(O)N(iBu)2 forms anionic five-coordinate oxorhenium(V) complexes by a ligand-exchange reaction of NBu4[ReOCl4] in methanol. In the absence of a base, the compounds were isolated as "betaine", [ReO(S4)], with the protonated nitrogen of the bridge serving as an internal "counterion". Two representatives have been fully characterized in both the solid and solution states and found to adopt the expected square-pyramidal coordination geometry. The equatorial plane is formed by four thiolate sulfur atoms, whereas the oxygen occupies the apical position. The orientation of the metal oxo group is exo in relation to the carbamido groups in both isomers. Both complexes are stereoisomeric regarding the junction of the triamine chain.
Our group previously synthesized 99mTc-labeled fatty acids suitable for myocardial metabolism and flow imaging. In this set of experiments, 29 new analogues were synthesized according to the 4 + 1 mixed ligand approach with some specific differences. Conventional 4 + 1 99mTc-fatty acids are built in the sequence: Tc-chelate, alkyl chain, and carboxylic group. We developed compounds following a new design with the sequence: carboxylic group, alkyl chain, Tc-chelate, and lipophilic tail. Therefore, the 99mTc-chelate was transferred to a more central position of the compound, aiming toward an improved myocardial profile and an accelerated liver clearance. In this context, several functional groups incorporated in the lipophilic tail section were tested to evaluate their influence on the compound's character. In addition to biodistribution studies in vivo, the myocardial first-pass extraction of the compounds was tested in an isolated Langendorff rat heart model. A satisfactory myocardial uptake of up to 20% of the injected dose (% ID) in the perfused heart and a fast liver clearance in vivo with only 0.29% ID/g at 60 min postinjection demonstrate that the induced molecular modifications affect the kinetics of 99mTc-radiolabeled fatty acid compounds favorably. From the data set, rules for estimating the biodistribution of fatty acids tracers are deduced.
In an attempt to develop new technetium-based radiopharmaceuticals for the noninvasive diagnosis of myocardial metabolism, we have synthesized three examples of novel metal-containing fatty acid derivatives according to the 3+1 mixed-ligand and the Schiff base/tricarbonyl design. The chelates contain the metal core in the oxidation states +5 and +1, respectively, and are attached to the end-position of a fatty acid chain. The complex formation was accomplished by ligand-exchange reactions with three different rhenium precursors, whereas the inactive rhenium metal was utilized as a surrogate of the technetium radionuclide. The molecular structures of the fatty acid complexes 7, 10 and 14 were determined by single-crystal X-ray diffraction analyses and impressively show a general problem in technetium tracer research, namely the significant structural alterations of bioactive molecules by coordination even to small metal chelates.
Novel technetium(III) mixed-ligand chelates for the design of lipophilic complexes stable in vivo
(2001)
Development of new radiopharmaceuticals based on rhenium-188 depends on finding appropriate ligands able to give complexes with high in vivo stability. Rhenium(III) mixed-ligand complexes with tetradentate/monodentate ('4 + 1') coordination of the general formula [Re(NS3)(PRR'R' ')] (NS3 = tris(2-mercaptoethyl)amine and derivatives thereof, PRR'R' ' = phosphorus(III) ligands) appear to be among the promising tools to achieve this goal. According to this approach, we synthesized and characterized a series of rhenium model complexes. In vitro stabilities of the corresponding rhenium-188 complexes were determined by incubating 2-3 MBq or alternatively 37 MBq of the complexes in phosphate buffer, human plasma, and rat plasma, respectively, at 22° C or 37° C, followed by checking the amount of 188ReO4- formed after 1 h, 24, and 48 h by thin-layer chromatography. The rate of perrhenate formation varied over a wide range, depending primarily on the nature of the phosphorus(III) ligand. Physicochemical parameters of the corresponding nonradioactive rhenium complexes were analyzed in detail to find out the factors influencing their different stability and furthermore to design new substitution-inert '4 + 1' complexes. Tolman's cone angle of phosphorus(III) ligands and the lipophilic character of the inner coordination sphere were found to be crucial factors to build up stable rhenium '4 + 1' complexes. Additional information useful to describe electronic and steric properties of these compounds were selected from electronic spectra (wavelength of the ReS charge-transfer band), cyclovoltammetric measurements (E° of the ReIII/ReIV couple), and NMR investigations (31P chemical shift of coordinated P(III) ligands).
New oxorhenium complexes with 2-(diphenylphosphanyl)-N-(2-thioethyl)benzamide (H2PNS) and trimethyl-, triethyl- and triphenyl-hydroxyl silylated monodentate thiols are reported. These new complexes have been prepared by reacting [NnBu4][Re(O)Cl4] with the tridentate H2PNS and the corresponding silylated thiol at room temperature. The characterization of the complexes involved elemental analysis, 31P and 1H NMR spectroscopies and X-ray crystallographic analysis for the triethyl-silylated Re complex.
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