Oxotechnetium Complexes Research Articles

Oxorhenium(V) and Oxotechnetium(V) Complexes of N3S Tetradentate Ligands with a Styrylpyridyl Functional Group: Toward Imaging Agents to Assist in the Diagnosis of Alzheimer's Disease.

Alzheimer's disease (AD) is associated with the presence of amyloid plaques in the brain mainly comprised of aggregated forms of amyloid-β (Aβ). Molecules radiolabeled with technetium-99m that cross the blood-brain barrier (BBB) and selectively bind to Aβ plaques have the potential to assist in the diagnosis of AD using single-photon emission computed tomography imaging. In this work, three new tetradentate ligands of pyridyl, amide, amine and thiol donors, featuring a styrylpyridyl group that is known to interact with amyloid plaques, were prepared. The new ligands formed charge-neutral and lipophilic complexes with the [Tc═O]3+ and [Re═O]3+ motifs, and two rhenium complexes were characterized by X-ray crystallography. The rhenium(V) complexes interact with synthetic Aβ1-40 and amyloid plaques on human brain tissue. Two of the new ligands were radiolabeled with 99mTc using a kit-based approach, and their biodistribution in wild-type mice was evaluated. The presence of amide donors in the tetradentate ligand increased the stability of the respective [Tc═O]3+ complexes but reduced brain uptake. While the complexes were able to cross the BBB, the degree of uptake in the brain was not sufficient to justify further investigation of these complexes.

Synthesis of Oxorhenium(V) and Oxotechnetium(V) Complexes That Bind to Amyloid-β Plaques.

Alzheimer's disease is characterized by the presence of amyloid plaques in the brain. The primary constituents of the plaques are aggregated forms of the amyloid-β (Aβ) peptide. With the goal of preparing technetium-99(m) complexes that bind to Aβ plaques with the potential to be diagnostic imaging agents for Alzheimer's disease, new tetradentate ligands capable of forming neutral and lipophilic complexes with oxotechentium(V) and oxorhenium(V) were prepared. Nonradioactive isotopes of technetium are not available so rhenium was used as a surrogate for exploratory chemistry. Two planar tetradentate N3O ligands were prepared that form charge-neutral complexes with oxorhenium(v) as well as a ligand featuring a styrylpyridyl functional group designed to bind to Aβ plaques. All three ligands formed complexes with oxorhenium(V), and each complex was characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography. The oxorhenium(V) complex with a styrylpyridyl functional group binds to Aβ plaques present in post-mortem human brain tissue. The chemistry was extrapolated to technetium-99(m) at the tracer level for two of the ligands. The resulting oxotechnetium(V) complexes were sufficiently lipophilic and charge-neutral to suggest that they have the potential to cross the blood-brain barrier but exhibited modest stability with respect to exchange with histidine. The chemistry presented here identifies a strategy to integrate styrylpyridyl functional groups into tetradentate ligands capable of forming complexes with [M═O](3+) cores (M = Re or Tc).

Synthesis and biological evaluation of a new triazole–oxotechnetium complex

A new triazole oxotechnetium chelating agent was synthesized via a 'Click-to-Chelate' strategy. In vivo evaluation of the corresponding (99m)Tc complex shows that the tracer exhibits very interesting properties for molecular imaging.

C–S Bond Cleavage during Reactions between N,N‐Diethylthiocarbamoyliminothianes and [MOCl4]– Complexes (M = Re, Tc)

Abstract[MOCl4]– complexes (M = Re, Tc) react with thianes derived from N‐[(diethylamino)(thiocarbonyl)]benzamidoyl chloride and 2‐mercaptophenol (HL1) and 2‐mercaptoaniline (HL2) under C–S bond cleavage and formation of oxorhenium(V) and oxotechnetium(V) complexes with the resulting decomposition products 2‐mercaptophenol and N‐[(dialkylamino)thiocarbonyl]‐N′‐2‐mercaptophenyl)benzamidine (H2L2a), respectively. The products, (NBu4)[ReO(S,O‐C6H4)2], [ReOCl(L2a)] and [TcO(L2a)] were obtained in good yields and isolated in crystalline form. Single‐crystal X‐ray studies reveal square‐pyramidal coordination environments with apical oxo ligands for all three product complexes under study.

Chelate oxorhenium to assemble new integrin antagonists

Assembly of independent chemical modules through oxorhenium coordination by a NS 2 + S chelation motif was applied to the synthesis of RGD (Arg-Gly-Asp) analogs. Modules were assembled through oxorhenium chelation to give a series of 18 metal complexes in good yields and satisfactory purities. Screening of these oxorhenium coordinates as antagonists of integrins αVβ3, αIIbβ3 and αVβ5 led to the identification of 3 bioactive compounds that exhibit submicromolar affinities for the 3 integrins. Preliminary studies showed that the corresponding oxotechnetium complexes are stable in mice plasma and therefore could be proposed for the molecular imaging of pathologies that overexpress integrins αVβ3 and αVβ5.

Synthesis, in vitro screening and in vivo evaluation of cyclic RGD analogs cyclized through oxorhenium and oxotechnetium coordination

A library of RGD tripeptide analogs cyclized through oxorhenium coordination by an NS 2/S chelation motif was synthesized. Screening towards integrins αVβ3, αIIbβ3 and αVβ5 led to the identification of 6 oxorhenium complexes that bind to integrin αVβ3 in the submicromolar range. In vivo evaluation of five of the corresponding oxotechnetium complexes using nude mice bearing a U87MG human tumor xenograft showed a significant and specific accumulation of radioactivity inside the tumor. The best results in vivo were obtained with complexes Tc-16 and Tc-50 that displayed a higher tumor accumulation and a lower distribution in other tissues relative to a reference cyclopentapeptide tracer.

Insight into Technetium Amidoxime Complex: Oxo Technetium(V) Complex of N-Substituted Benzamidoxime as New Basic Structure for Molecular Imaging

In search of benzamidoxime (BHam) derivatives that provide a single (99m)Tc-labeled compound of high in vivo stability, we synthesized three N-alkyl compounds of benzamidoxime (BHam) ligand. They provided a single (99m)Tc-labeled compound by ligand exchange reaction of (99m)Tc-glucoheptonate in high radiochemical yields (over 95% at MBHam concentration of 1 × 10(-5) M). (99m)Tc-N-methyl benzamidoxime ((99m)Tc-MBHam) showed higher stability than the parental (99m)Tc-BHam. The complex of this compound with (99g)TcO(3+) ion was prepared, isolated, and characterized by FT-IR and NMR spectra as well as X-ray diffraction. (99g)Tc-MBHam crystallized in an orthorhombic space group Pna2(1) with a = 13.4823(5), b = 15.5410(7), c = 7.7907(3) Å, V = 1632.39(11) Å(3), and Z = 4. The (99g)Tc complex possessed square base pyramid coordination geometry. The equatorial plane was formed by two-amine nitrogen and two-oxime oxygen atoms in trans position, while the oxo core of the technetium(V) occupied the apical position. The (99g)Tc-MBHam proved to be identical with the (99m)Tc-MBHam prepared at the no-carrier-added level by comparison of their HPLC profiles.

New oxorhenium (V) complex with an imidazol [NN] /hydantoin [SN] mixed ligand system, and radiochemical behavior of its oxotechnetium (V) complex analog

New oxorhenium (V) complex with an imidazol [NN] /hydantoin [SN] mixed ligand system, and radiochemical behavior of its oxotechnetium (V) complex analog

New oxorhenium (V) complex with an imidazol [NN] /hydantoin [SN] mixed ligand system, and radiochemical behavior of its oxotechnetium (V) complex analog

A [ReO(Imz)(Hyd)(H2O)2OH] complex was successfully synthesized by the ligand exchange method using oxorhenuim citrate and an imidazole /Hydanton mixed ligand system. Geometry optimization of complex has been carried out using DFT at the B3LYP/LANL2DZ functional in singlet state. B3LYP predicated infrared spectrum of the geometrically optimized structure using the same level of the theory and the same base set showed good agreement with experimentally observed values. The spin allowed singlet-singlet electronic transition of the [ReO(Imz)(Hyd) (H2O)2OH] complex was calculated with time dependent density function theory (TD-DFT) and the UV-Vis spectra has been discussed on this basis. The complex was characterized using microanalysis and IR, UV-Vis, NMR and mass spectroscopic. The technetium tracer [99mTcO(Imz)(Hyd) (H2O)2OH] has also been synthesized by two methods using 99mTc-gluconate as a precursor or; by direct reduction. The radiochemical purity of the complex was over 95% as measured by thin layer chromatography. In vitro studies showed that the complex possessed good stability under physiological conditions. The partition coefficient indicated that the complex hydrophilic and the electrophoresis results showed that the complex cationic. Biodistrbution in mice showed that the complex accumulated in heart uptake of 9.53±3.87 % ID/gm at 5 min and good retention (6.37±1.21) % ID/gm at 60 min. One hour after the injection, the heart/liver, heart/lung and heart/blood radioactivity ratios were 0.46, 1.04 and 0.56, respectively. These findings indicate that the complex might be suitable for myocardial imaging.

Oxotechnetium(V) Complexes with a Novel Class of Tridentate Thiosemicarbazide Ligands

A novel tridentate thiosemicarbazide-type ligand class with an SNS donor set, H(2)L(1), was prepared by reactions of N-[N',N'-dialkylamino(thiocarbonyl)]benzimidoyl chlorides with thiosemicarbazides. H(2)L(1) ligands readily react with (NBu(4))[TcOCl(4)] in MeOH under the formation of red oxotechnetium(V) complexes of composition [TcOCl(L(1))]. The monomeric, five-coordinate compounds are air-stable and bind (L(1))(2-) tridentate in the equatorial coordination sphere. The compounds represent the first examples of oxotechnetium(V) complexes with NS chelate-bonded thiosemicarbazones.

Rhenium and Technetium Complexes with TridentateN-[(N′′,N′′-Dialkylamino)(thiocarbonyl)]-N′-substituted Benzamidine Ligands

N-[(Dialkylamino)(thiocarbonyl)]benzimidoyl chlorides react with functionalized amines such as 2-aminophenol, 2-methylaminopyridine, and 2-aminobenzoic acid in clean and high-yield procedures with the formation of the novel tridentate N-[(N'', N''-dialkylamino)(thiocarbonyl)]- N'-substituted benzamidine ligands H2L1, HL2, and H2L3. By starting from (NBu4)[MOCl4] (M = Re, Tc) or [ReOCl3(PPh3)2] and H2L1, a series of oxorhenium(V) and oxotechnetium(V) complexes of the composition [MOCl(L1)] were synthesized and characterized by spectroscopic methods and X-ray crystallography. The monomeric, five-coordinate compounds are air-stable and bind (L1)(2-) tridentate in the equatorial coordination sphere. Dimeric products of the compositions [(ReOCl(L2))2O] and [ReOCl(L3)]2 were isolated during reactions with HL2 and H2L3. While dimerization in [(ReOCl(L2))2O] is established via an oxo bridge, the metal atoms in [ReOCl(L3)]2 are connected by the carboxylic group of the ligand, and the product represents the first example of a high-oxidation state rhenium complex displaying such a bonding feature.

Synthesis and structural characterization of neutral “3 + 2” oxorhenium and oxotechnetium complexes of the 2-mercaptoethyl- N-glycine (SNO)/2,2′-bipyridine (NN) mixed ligand system

Neutral, hexacoordinated “3 + 2” mixed ligand oxorhenium ( 1) and oxotechnetium ( 2) complexes of the general formula MO[SNO][NN], where M = Re or 99Tc, SNO is 2-mercaptoethyl- N-glycine and NN is 2,2′-bipyridine ( bpy), were synthesized by simultaneous action of the tridentate SNO and the bidentate NN ligand on ReOCl 3(PPh 3) 2 or 99TcO-gluconate precursors in a 1:1:1 molar ratio. Both complexes were characterized by elemental analysis, IR and NMR spectroscopy. X-ray structure determination of rhenium complex 1 revealed a distorted octahedral coordination geometry where the SNO donor atoms of the tridentate ligand and one bpy nitrogen atom occupy the equatorial positions of the octahedron, whereas the second bpy nitrogen atom and the oxo-group fill the apical positions.

Preparation and Biological Characterization of Isomeric 188Re(V) Oxocomplexes with Tetradentate S4 Ligands Derived from meso-Dimercaptosuccinic Acid for Labeling of Biomolecules

A new type of tetradentate S4 ligand has been synthesized by bridging two molecules of meso-2,3-dimercaptosuccinic acid for stable binding and easy conjugation of rhenium-188 to tumor targeting structures. The stereoisomeric tetrathiolato S4 ligands form very robust anionic five-coordinated oxorhenium(V) and oxotechnetium(V) complexes. Two routes for the preparation of the (188)Re(V) oxocomplexes with (iBu)2N(O)C-C(SH)C(SH)C(O)NH(CH2)3NH(CH2)3NHC(O)C(SH)C(SH)C(O)N(iBu)2 (ligand 1) and its hydrophilic crown ether derivative (ligand 2) were tested and optimized. Several isomers were separated by HPLC from the preparation solutions and characterized in vitro and in vivo. The identity of the species obtained was determined by comparison with the HPLC profiles of reference (185/187)Re analogues and (99/99m)Tc complexes which were characterized by ESI-MS. All of them were absolutely stable in rat and human plasma solutions. Challenge experiments with cysteine corroborated the high inertness of the isomers toward ligand exchange reactions. Various in vivo samples, taken off at different times from blood, intestine, and urine of rats, confirmed the high in vivo stability of the (188)Re-S4 complexes. Biodistribution studies using male Wistar rats were performed and exhibited a high uptake and fast clearance from the liver of the more lipophilic cis and trans isomers of complex I (log P(o/w) between 1.5 and 1.7), whereas the isomers of the hydrophilic complex II (log P(o/w) about -1.75) were rapidly excreted via the renal and the hepatobiliary pathway. The low level of activity in the stomach confirms good in vivo stability. Thus, these new (188)Re-S4 complexes fulfill the requirements for a stable and high specific activity labeling of biomolecules with rhenium-188.

99mTcOAADT]-(CH2)2-NEt2: A Potential Small-Molecule Single-Photon Emission Computed Tomography Probe for Imaging Metastatic Melanoma

Evaluation of [99mTc]oxotechnetium(V) complexes of the amine-amide-dithiol (AADT) chelates containing tertiary amine substituents as small-molecule probes for the diagnostic imaging of metastatic melanoma has shown that technetium-99m-labeled AADT-(CH2)2-NEt2 (99mTc-1) has the highest tumor uptake and other favorable biological properties. We have, therefore, assessed this agent in a more realistic metastatic melanoma model in which, after i.v. tail injection, a highly invasive melanoma cell line, B16F10, forms pulmonary tumor nodules in normal C57BL6 mice. Small melanotic lesions develop in the lungs and, on histologic examination, appear as small black melanoma colonies, increasing in size and number with time after tumor cell injection. Groups of mice received tumor cell inocula of 2 x 10(5), 4 x 10(5), or 8 x 10(5) B16F10 cells; 14 days later, 2 hours after 99mTc-1 administration, lung uptake of 2.83 +/- 0.21%, 3.63 +/- 1.07%, and 4.92 +/- 1.61% injected dose per gram of tissue (% ID/g), respectively, was observed, compared with normal lung uptake of 2.13 +/- 0.2% ID/g (P < 0.05). Additionally, a higher level of 99mTc-1 accumulation was seen 17 days after tumor cell inoculation as the lung lesions grew. These in vivo studies coupled with additional in vitro and ex vivo assessment show that 99mTc-1 has high and specific uptake in melanoma metastases in lungs and can potentially follow the temporal growth of these tumors.

Synthesis and structural characterization of new oxorhenium and oxotechnetium complexes with XN2S-tetradentate semi-rigid ligands (X = O, S, N)

Twelve novel oxo-technetium and oxo-rhenium complexes based on N2S2-, N2SO- or N3S-tetradentate semi-rigid ligands have been synthesised and studied herein. By reacting the ligands with a slight excess of suitable [MO]3+ precursor (ReOCl3(PPh3)2 or [NBu4][99gTcOCl4]), the monoanionic complexes of general formula [MO(Ph-XN2S)]- could be easily produced in high yield. The complexes have been characterized by means of IR, electrospray mass spectrometry, elemental analysis, NMR and conductimetry. The crystal structures of [PPh4][ReO(Ph-ON2S)] 1b and [NBu4][99gTcO(Ph-ON2S)] 1c have been established. The [MO]3+ moiety was coordinated via the two deprotonated amide nitrogens, the oxygen and the terminal sulfur atoms in 1b and 1c. In both compounds, the ON2S coordination set is in the equatorial plane, and the complexes adopted a distorted square-pyramidal geometry with an axial oxo-group. The chemical and structural identity of the different prototypic complexes (rhenium, 99gTc complexes and their corresponding 99mTc radiocomplexes) have been also established by a comparative HPLC study.

Synthesis and biological evaluation of silylated mixed-ligand 99mTc complexes with the [PNS/S] donor atom set

New oxotechnetium complexes of general formula [ 99mTc(O)(PNS)(S(CH 2) n OSiR 3)] ( 4– 6) were synthesized by direct reduction of [ 99mTcO 4] − with stannous chloride, in the presence of the tridentate heterofunctionalized phosphine H 2PNS and of the monodentate silylated thiols [HS(CH 2) n OSiR 3] ( n=2, R=Ph ( 1); n=3, R=Ph ( 2); n=3, R=Et ( 3)). The mixed-ligand rhenium and technetium complexes of general formula [M(O)(PNS)(S(CH 2) n OH)] ( n=2: M= 99mTc, ( 7), M=Re, ( 7a); n=3: M= 99mTc, ( 8), M=Re, ( 8a)) were also prepared. All the 99mTc complexes were obtained with high radiochemical purity (>95%), after purification by HPLC, and were characterized by comparison of their HPLC profiles with the ones obtained for the corresponding Re compounds. The silylated compounds 4– 6 are stable in phosphate saline buffer (PBS) pH 7.4, rat plasma, human serum and whole blood, and do not bind to plasmatic proteins, and also do not challenge with glutathione. The biological behavior of [ 99mTc(O)(PNS)(S(CH 2) n OH)] ( 7, 8) and [ 99mTc(O)(PNS)(S(CH 2) n OSiR 3)] ( 4– 6) was studied. The effect of the pH on the cleavage of the O-Si bond in complexes 4– 6 was also evaluated.

Neutral oxorhenium(V) and oxotechnetium(V) complexes with novel amide thioether dithiolate ligands derived from cysteine

AbstractBifunctional ligands able to form neutral complexes with radioactive technetium and rhenium and to couple to biological relevant anchor groups play an important role in the design of new radiopharmaceuticals for diagnosis and therapy. A novel tetradentate amide thioether dithiolate ligand HS-CH2CH2-S-CH2CONH-CH(COOR)CH2SH (H3SNSS) with R=CH3, C10H21was synthesized that forms stable complexes with technetium and rhenium in oxidation state V. The molecular structures of the rhenium and technetium complexes MO(SNSS) were determined by X-ray structural analysis and show that the metal coordination number is five and the coordination polyhedron is between square-pyramidal and trigonal-bipyramidal. The pendent ester group allows coupling of the chelate unit at biologically relevant anchor groups. As a relevant representative the X-ray structural analysis of the rhenium decylester complex was carried out. The complex formation with Tc at the n.c.a. level and186Re at 10-6M level is described.

Conformational investigation of benzylhydroxamamide, its oxotechnetium(V) complexes and determination of their reaction energies

The structures of benzylhydroxamamide (BHam, LH) conformers, deprotonated (L −) species and their technetium complexes have been obtained by geometry optimizations using Hatree–Fock at different basis sets and density functional theory calculations at B3LYP/6-31G(d) level of theory. Two hydroxyimino and ten hydroxyamino conformers of BHam have been found. Conformational pathways of all stable BHam conformers and their oxo-Tc(V) complexes have been investigated. The tautomerization between hydroxyimino and hydroxyamino tautomers is an endothermic reaction, with ΔH o=7.38 kcal/mol and its equilibrium constant log K=−5.70, at 298.15 K. The stabilization energies of oxo-Tc(V) complexes existing as [(LH) 2TcO] +3, [L 2TcO] + of C 2 and [L 2TcO] + of C 2v conformers have been determined at HF/3-21G level of theory. The optimized geometry of hydroxyimino tautomer is the most stable species and shows good agreement with X-ray crystallographic data.

Novel 3+1 mixed-ligand Technetium-99m complexes carrying dipeptides as monodentate ligands

Novel mixed ligand oxotechnetium complexes of the type [ 99mTcO(SSS)(SR)], in which the SR monodentate ligand is derived from dipeptides gly-gly, phe-gly and ala-gly, have been synthesized. These complexes, which have a molecular weight above 300, a lipophilic moiety, [TcO(SSS)] +, and an ionizable group separated from the lipophilic moiety by a spacer, have been obtained in 70-95% radiochemical yield. These compounds were prepared using 99mTc-tartrate as the precursor and Sn 2+ as the reducing agent. The identity of the [ 99mTcO(SSS)(SR)] complexes has been established by HPLC comparison with the analogous oxorhenium complexes. The nature of the monodentate co-ligand strongly affects the stability of the 99mTc-complexes and their biodistribution. Complex 3b is the most stable in vitro presenting the highest blood clearance, a high liver uptake and a selective hepatobiliary excretion (54.5% ID at 15 min post-injection, and 69.3% ID at 60 min post injection). The results obtained show that 3b have reasonable stability and in vivo properties that may be useful for peptide labeling.

Synthesis and Characterization of Oxorhenium and Oxotechnetium Complexes with a Novel Tetradentate N3O Bifunctional Agent

AbstractThe novel tetradentate N3O bifunctional agent 3‐hydroxy‐4‐[2‐(2′‐pyridinecarboxamido)acetylamino]benzoic acid (1), reacts with [Bu4N][ReOCl4] or [Bu4N][99gTcOCl4] in EtOH resulting in neutral and stable oxorhenium 2 or oxotechnetium‐99 g 3 complexes. Both complexes were characterized by elemental analysis, IR, 1H and 13C NMR spectroscopy. X‐ray analysis of 2 showed that the rhenium atom is pentacoordinate presenting a distorted square‐pyramidal coordination geometry. The analogous oxotechnetium‐99m complex 4 was also prepared quantitatively by the reaction of ligand 1 with Na99mTcO4 in isotonic saline using tin chloride as reducing agent. Its identity was established by chromatographic comparison to the oxorhenium 2 and oxotechnetium 3 complexes. (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2003)