Radiosynthesis and evaluation of novel [99mTc(I)]+ and [99mTc(I)(CO)3]+ complexes with a 4-nitroimidazole isocyanide for imaging tumor hypoxia

[^99mTc(I)]⁺ and [^99mTc(I)(CO)₃]⁺ complexes with isocyanide exhibit high stability, which makes them suitable platforms to develop novel ^99mTc radiopharmaceuticals. To develop novel ^99mTc radiotracers for imaging hypoxia, in this study, a novel L ligand (4-nitroimidazole isocyanide derivative) was synthesized and labelled using [^99mTc(I)]⁺ core and [^99mTc(I)(CO)₃]⁺ core to produce [^99mTc(L)₆]⁺ and [^99mTc(CO)₃(L)₃]⁺ with high yields. To verify the structure of the ^99mTc complexes, corresponding rhenium analogues were synthesized and characterized. Both of the ^99mTc complexes were stable and hydrophilic. in vitro cellular uptake results showed they could exhibit good hypoxic selectivity. The evaluation of biodistribution in mice bearing S180 tumors indicated both of them could accumulate in tumor. Between them, [^99mTc(L)₆]⁺ exhibited higher tumor uptake and tumor/non-target ratio than [^99mTc(CO)₃(L)₃]⁺. Further, single photon emission computed tomography (SPECT) imaging studies of [^99mTc(L)₆]⁺ indicated an obvious accumulation in tumor and the value of the region-of-interest (ROI) ratio of the uptake for the tumor site to the corresponding non-tumor region was 5.64 ± 0.52. The above results suggested [^99mTc(L)₆]⁺ would be a potential tracer for imaging tumor hypoxia.     

Chemical and biological evaluation of 99mTc (CO)3 and 99mTc complexes of some IDA derivatives

The confirmation that N-substituted imidodiacetic acids, as small and simple ligand systems containing amines and carboxylic acids, could be coordinated to the tricarbonyl core and form inert complexes with [^99mTc (CO)₃(H₂O)₃]⁺, is demonstrated. The HPLC quality control results of ^99mTc-carbonyl tagged IDA molecules, performed by gradient HPLC, have shown that HIDA, EHIDA and p-butyl-IDA form complexes with [^99mTc(CO)₃(H₂O)₃]⁺, with a labeling yield of ~90% for each of ^99mTc(CO)₃ IDA derivatives. However, the changes in the structure of labeled compounds, e.g., EHIDA, influence the changes in the biological behavior. In comparison with ^99mTc-EHIDA, the biliary excretion of ^99mTc(CO)₃ EHIDA was lower, but the urinary excretion higher. This revised version was published online in July 2006 with corrections to the Cover Date.     

Synthesis, radiolabeling and biodistribution studies of [99mTc(CO)3(MN-TZ-BPA)]+ in tumor-bearing mice

This study reports the synthesis, radiolabeling and preliminary biodistribution results of [^99mTc(CO)₃(MN-TZ-BPA)]⁺ in tumor-bearing mice. The novel nitroimidazole derivative was successfully synthesized by conjugation of bis(pyridin-2-ylmethyl)amine (BPA) to 2-methyl-5-niroimidazole via “click” reaction. The ligand could be labeled by [^99mTc(CO)₃]⁺ core in high yield to get [^99mTc(CO)₃(MN-TZ-BPA)]⁺, which was very hydrophilic and was stable at room temperature. Biodistribution studies in tumor-bearing mice showed that [^99mTc(CO)₃(MN-TZ-BPA)]⁺ accumulated in the tumor with certain initial uptake while poor retention. The rapid clearance from normal organs with favorable tumor/muscle ratios warrants further research to improve tumor targeting efficacy and pharmacokinetic profile of radiolabeled nitroimidazoles by structural modification.     

Synthesis and preliminary biological evaluation of 99mTc(CO)3-labeled pegylated 2-nitroimidazoles

This work reports the synthesis, radiolabeling and preliminary biodistribution results in tumor-bearing mice of ^99mTc(CO)₃-labeled pegylated (PEG) 2-nitroimidazoles for tumor hypoxia imaging. The novel 2-nitroimidazole derivatives were successfully synthesized by conjugation of tridendate chelators to 2-nitroimidazole via PEG₃ linker. Radiolabeling was performed in high yield with [^99mTc(CO)₃]⁺ core to get cationic [^99mTc(CO)₃(BPA-PEG₃-NIM)]⁺, neutral [^99mTc(CO)₃(AOPA-PEG₃-NIM)] and anionic [^99mTc(CO)₃(IDA-PEG₃-NIM)]^? respectively, all of which were hydrophilic and stable at room temperature. Biodistribution studies in tumor-bearing mice showed that ^99mTc(CO)₃-labeled pegylated 2-nitroimidazoles accumulated in the tumor with low uptake. ^99mTc-chelate and charge had significant impact on partition coefficient, radiotracer tumor uptake and pharmacokinetic properties. The results indicate the need for synthetic modification of the parent 2-nitroimidazole derivatives and the ^99mTc-chelate with a view to improve the tumor targeting efficacy and in vivo kinetic profiles.     

Characterization of 99mTc(CO)3-iminodiacetic acid (IDA) and its comparison with 99mTc-(IDA)2 using compounds for hepatobiliary scintigraphy

The organometallic precursor of fac-[^99mTc(CO)₃(H₂O)₃]⁺ has attracted much attention because of the robustness and small size of Tc(I)-tricarbonyl complexes compared to Tc(V) complexes and the good labeling affinity with a variety of donor atoms. Among various ligand systems, an iminodiacetic acid (IDA) was proven as a good chelating group to form a Tc(III)-compelx as well as has been shown its potential as a chelating system for fac-[^99mTc(CO)₃] precursor. In an attempt to confirm the similarity and the difference between ^99mTc(CO)₃-IDA and ^99mTc-(IDA)₂-complex, M(CO)₃-IDA (M = ^99mTc, Re) complexes of disofenin, mebrofenin and N-(3-iodo-2,4,6-trimethyl phenylcarbamoylmethyl) iminodiacetic acid were prepared, and the biological evaluation of ^99mTc(CO)₃-disofenin was performed. The ^99mTc(CO)₃-IDA complexes were prepared with a high radiolabeling yield (>98%) in a quantitative manner and showed a negative charge. The in vivo pharmacokinetic behavior of ^99mTc(CO)₃-disofenin showed a similar biological activity to ^99mTc-(disofenin)₂ in that those complexes were quickly cleared from the blood by the hepatocytes and excreted into the gallbladder and intestine. Accordingly, the ^99mTc(CO)₃-IDA derivatives of disofenin and mebrofenin might be used as hepatobiliary imaging agents. Since an IDA is a promising chelator for ^99mTc-based radiopharmaceutical and the biological properties of ^99mTc(CO)₃-IDA derivative shows similar to that of ^99mTc-complex, a biomolecule containing IDA can be freely radiolabeled with fac-[^99mTc(CO)₃]-precursor or ^99mTc. However, the radiolabeling efficiency and the biological behavior demonstrates the favorable properties of ^99mTc(CO)₃-IDA compound for the development of a new imaging agent.     

Evaluation and comparison of 99mTc-labeled d-glucosamine derivatives with different 99mTc cores as potential tumor imaging agents

Isocyanide is a strong coordination ligand that can coordinate with [^99mTc(I)(CO)₃]⁺ core and [^99mTc(I)]⁺ core to produce stable ^99mTc complexes, therefore developing a ^99mTc-labeled isocyanide complex for single-photon emission computed tomography (SPECT) imaging is considered to be of great interest. In order to develop potential tumor imaging agents with satisfied tumor uptake and suitable pharmacokinetic properties in vivo, a novel d -glucosamine isocyanide derivative, 4-isocyano-N-(2,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)butanamide (CN3DG), was synthesized and radiolabeled with [^99mTc(I)]⁺ and [^99mTc(CO)₃]⁺ cores to obtain [^99mTc(CN3DG)₆]⁺ and [^99mTc(CO)₃(CN3DG)₃]⁺ in high radiolabeling yields (>95%). Both of the complexes showed good hydrophilicity and great stability in vitro. Cell uptake studies performed in S180 cells demonstrated they were transported into cells by glucose transporters. Biodistribution studies of the two complexes in mice bearing S180 tumor showed they had high tumor uptakes and rapid clearance from muscle and blood so that the tumor/blood and tumor/muscle ratios were high. By comparison, [^99mTc(CN3DG)₆]⁺ was superior to [^99mTc(CO)₃(CN3DG)₃]⁺ in regard to tumor uptake, tumor/blood and tumor/liver ratios. S180 tumors could be seen clearly from the SPECT/CT images with [^99mTc(CN3DG)₆]⁺. Considering its favorable properties, [^99mTc(CN3DG)₆]⁺ would be a promising tumor imaging agent and needs to be further studied.     

Preparation and preliminary evaluation of a tris-metronidazole-<Superscript>99m</Superscript>Tc(CO)<Subscript>3</Subscript> complex for targeting tumor hypoxia

Conventional ^99mTc-radiopharmaceuticals for the detection of tumor hypoxia generally possess a single nitroimidazole moiety. Herein, we report the synthesis and evaluation of a ^99mTc-complex with three-nitroimidazole moieties in an attempt to improve hypoxic cell detection. Isocyanide derivative of metronidazole (MetroNC) was synthesized and subsequently radiolabeled with [^99mTc(CO)₃(H₂O)₃]⁺ precursor complex, wherein the three labile water molecules were replaced with MetroNC ligand to form a pseudo-octahedral [^99mTc(CO)₃(MetroNC)₃]⁺ complex. Analysis of corresponding Re(CO)₃-analog prepared in macroscopic scale confirmed the formation of expected complex. Cyclic voltammetric studies of [Re(CO)₃(MetroNC)₃]⁺ complex showed no significant change in single-electron reduction potential (SERP) of MetroNC ligand (??0.96 V) upon forming the [Re(CO)₃(MetroNC)₃]⁺ complex (??0.90 V). In vitro studies in Chinese hamster ovary (CHO) cells showed three-fold preferential accumulation of [^99mTc(CO)₃(MetroNC)₃]⁺ complex in hypoxic cells over normoxic cells. Biodistribution studies of [^99mTc(CO)₃(MetroNC)₃]⁺ complex in Swiss mice bearing fibrosarcoma tumor showed tumor uptake and steady retention till 60 min post injection. Present study constitutes a novel design approach towards development of a ^99mTc-radiopharmaceutical for hypoxia imaging application, which could be extended to other potential nitroimidazole ligands.     

Synthesis and biodistribution of 99mTc(CO)3-DMSA-MIBI in mice

Mixed ligand fac-tricarbonyl complex of [^99mTc(CO)₃-DMSA-MIBI] has been prepared starting from the precursor [^99mTc(OH₂)₃(CO)₃]⁺. The complex can be obtained in good yield and purity in a two-step procedure by first attaching meso-2,3-dimercaptosuccinic acid (DMSA, HOOCCH(SH)CH(SH)COOH) with [^99mTc(OH₂)₃(CO)₃]⁺, followed by addition of MIBI [tetrakis-2-methoxyisobutylisonitrile (CH₃OC(CH₃)₂CH₂-N≡C) copper(I) tetrafluoroborate] solution. The complex was characterized by TLC and HPLC and was studied by means of octanol-water partition coefficient, electrophoresis, stability in vitro, and normal mice experiment. Biodistribution in mice demonstrated that the complex showed higher myocardial uptake after 0.5-hour p.i. The ratios of heart/liver (%ID/g) in the case of ^99mTc(CO)₃-DMSA-MIBI was higher (1.88) than that observed in case of ^99mTc-MIBI¹ (0.93) after 0.5-hour p.i. (P<0.05). Results showed that the complex may be developed to a novel myocardial perfusion-imaging agent.     

Synthesis and biodistribution of the <Superscript>99m</Superscript>Tc(CO)<Subscript>3</Subscript>-DEDT complex as a potential new radiopharmaceutical for brain imaging

The ^99mTc(CO)₃(H₂O)-DEDT complex was prepared by a two-step procedure involving the preparation of the precursor fac-[^99mTc(CO)₃(H₂O)₃]⁺, followed by the addition of sodium salt of diethyl dithiocarbamate (DEDT). The radiochemical purity (RCP) of the product was over 90% as measured by thin layer chromatography (TLC). No decomposition of the complex at room temperature was observed over a period of 6 hours. Its partition coefficient indicated that it was a lipophilic complex. The electrophoresis results showed the complex was neutral. Biodistribution in mice demonstrated that the complex can penetrate the intact blood-brain barrier (BBB) and the brain uptake (ID%/g) was 4.22 at 5-minute post-injection, suggesting the complex may lead to a further development of the radiopharma ceutical as a brain perfusion tracer.     

Synthesis, Radiolabelling and in vitro Stability Study of 99mTc(CO)+3 Labeled Dendrimer PAMAM-Folic Acid Conjugate

Dendrimer polyamidoamine generation five‐folic acid conjugate was synthesesed and radiolabelled with fac‐[^99mTc(CO)₃(H₂O)₃]⁺, its in vitro stability was evaluated further. Both of the labeling yield and radiochemical purity of the G5‐FA‐DTPA‐^99mTc(CO)₃ conjugate exceeded 95%. More than 95.7% and 93.1% of the conjugate still keeps its original structure in PBS and new‐born calf serum solution respectively.     

S‐Functionalized Cysteine: Powerful Ligands for the Labelling of Bioactive Molecules with Triaquatricarbonyltechnetium‐99m(1+) ([99mTc(OH2)3(CO)3]+)

S‐Alkylated cysteines are used as efficient tridentate N,O,S‐donor‐atom ligands for the fac‐[M(CO)₃]⁺ moiety (M=^99mTc or Re). Reaction of (Et₄N)₂[ReBr₃(CO)₃] ( 3 ) with the model S‐benzyl‐L ‐cysteine ( 2 ) leads to the formation of [Re( 2′ )(CO)₃] ( 4 ) as the exclusive product ( 2′ =C‐terminal anion of 2 ). The tridentate nature of the alkylated cysteine in 4 was established by X‐ray crystallography. Compound 2 reacts with [^99mTc(OH₂)₃(CO)₃]⁺ under mild conditions (10⁻⁴ M , 50°, 30 min) to afford [^99mTc( 2′ )(CO)₃] ( 5 ) and represents, therefore, an efficient chelator for the labelling of biomolecules. L ‐Cysteine, S‐alkylated with a 3‐aminopropyl group (→ 7 ), was conjugated via a peptide coupling sequence with Coα‐[α‐(5,6‐dimethyl‐1H‐benzimidazolyl)]‐Coβ‐cyanocobamic b‐acid ( 6 ), the b‐acid of cyanocob(III)alamin (vitamin B₁₂) (Scheme 3). More convenient was a one‐pot procedure with a derivative of vitamin B₁₂ comprising a free amine group at the b‐position. This amine 15 was treated with NHS (N‐hydroxysuccinimide)‐activated 1‐iodoacetic acid 14 to introduce an I‐substituent in vitamin B₁₂. Subsequent addition of unprotected L ‐cysteine resulted in nucleophilic displacement of the I‐atom by the S‐substituent, affording the vitamin B₁₂ alkylated cysteine fragment 17 (Scheme 4). The procedure was quantitative and did not require purification of intermediates. Both cobalamin–cysteine conjugates could be efficiently labelled with [^99mTc(OH₂)₃(CO)₃]⁺ ( 1 ) under conditions identical to those of the model complex 5 . Biodistribution studies of the cobalamin conjugates in mice bearing B10‐F16 melanoma tumors showed a tumor uptake of 8.1±0.6% and 4.4±0.5% injected dose per gram of tumor tissue after 4 h and 24 h, respectively (Table 1).     

Exploring the nitrosyl-approach: “Re(CO)2(NO)”- and “Tc(CO)2(NO)”-complexes provide new pathways for bioorganometallic chemistry

Nitrosylation reactions are rare in the context of low valent Re(I)- and Tc(I)-tricarbonyl complexes so far. We herein describe a method for the conversion of a “M(CO)₃-moiety” (M = Re, Tc) into a dicarbonyl-nitrosyl moiety “M(CO)₂NO”, the synthesis of important precursor complexes and intermediates and possible applications for this new kind of Re- and Tc-chemistry.The behavior of the complex [ReCl₃(CO)₂(NO)]⁻ in water was studied in detail and compared to that of [ReCl₃(CO)₃]²⁻. Contrary to the conversion of [ReCl₃(CO)₃]²⁻ to the mixed aquo-carbonyl complex [Re(OH₂)₃(CO)₃]⁺ in water, one chloride remains initially bound to the metal center in the dicarbonyl-nitrosyl complex, making [ReCl(OH₂)₂(CO)₂(NO)]⁺ the main species for further reactions. In this context, we isolated and characterized the complex [Re(μ₃-O)(CO)₂(NO)]₄. Examples of complexes with different bi- and tridentate ligands based on ReCl₃(CO)₂(NO)]⁻ are discussed.For the development of potential new radiopharmaceuticals we also adapted the nitrosylation technique to the n.c.a. level with ^99mTc. [^99mTc(OH₂)₃(CO)₃]⁺ served as starting material to form a ^99mTc(CO)₂(NO)-core. Labelling reactions with ligands such as iminodiacetic acid (IDA), nitrilotriacetic acid (NTA) and diethylenetriamine pentaacetic acid (DTPA) were performed, resulting in the complexes [^99mTc(IDA)(CO)₂(NO)], [^99mTc(NTA)(CO)₂(NO)] and [^99mTc(DTPA)(CO)₂(NO)]. In this way, the “nitrosyl-approach” adds a new and challenging synthetic tool to the already established organometallic chemistry of Re- and Tc-tricarbonyl complexes.     

Radiosynthesis and in vitro evaluation of 99mTc(CO)3-labeled folic acid derivative

The over-expression of folate receptors in variety of neoplastic tissues makes radiolabeled folate conjugates potential agents for imaging and therapy of such cancers. With the aim of preparing an imaging agent for targeting folate receptors, folic acid has been conjugated with homocysteine for complexation with [^99mTc(CO)₃(H₂O)₃]⁺ core. The radiolabeled complex of the homocysteine-folate could be obtained in >95% radiochemical yield as observed by HPLC. Stability of complex in saline was studied and challenge studies with histidine and cysteine revealed kinetic stability of the complex. Lipophilicity of the radiolabeled complex (log P) was found to be 0.45. In vitro uptake of ^99mTc(CO)₃-labeled folic acid derivative was studied in KB cells and inhibition studies were carried out using ³H-folic acid and cold homocysteine–folate conjugate. The in vitro studies indicated loss of binding affinity of the derivative towards folate receptors.     

Comparative Study of a Series of 99mTc(CO)3 Mannosylated Dextran Derivatives for Sentinel Lymph Node Detection

Sentinel lymph node detection (SLND) is rapidly entering common practice in the management of patients with tumors. The introduction of mannose molecules to ^99mTc-labeled dextrans, so far, showed that the sentinel node could trap these agents due to their recognition by the mannose receptors of lymph node macrophages. The current study aimed to synthesize, characterize, and biologically evaluate a series of mannosylated dextran derivatives labeled with ^99mTc for potential use in SLND. The compounds were designed to have a dextran with a molecular weight of 10–500 kDa as a backbone, S-derivatized cysteines, efficient SNO chelators, and mannose moieties for binding to mannose receptors. They were successfully synthesized, thoroughly characterized using NMR techniques, and labeled with the fac-[^99mTc(CO)₃]⁺ synthon. Labeling with high yields and radiochemical purities was achieved with all derivatives. In vivo biodistribution and imaging studies demonstrated high uptake in the first lymph node and low uptakes in the following node and confirmed the ability to visualize the SLN. Among the compounds studied, ^99mTc-D75CM demonstrated the most attractive biological features, and in combination with the high radiochemical yield and stability of the compound, its further evaluation as a new radiopharmaceutical for sentinel lymph node detection was justified.     

To Sandwich Technetium: Highly Functionalized Bis-Arene Complexes [99mTc(η6-arene)2]+ Directly from Water and [99mTcO4]−

The labeling of (bio)molecules with metallic radionuclides such as ^99mTc demands conjugated, multidentate chelators. However, this is not always necessary since phenyl rings can directly serve as integrated, organometallic ligands. Bis-arene sandwich complexes are generally prepared by the Fischer–Hafner reaction. In extension of this, we show that [^99mTc(η⁶-C₆R₆)₂]⁺-type complexes are directly accessible from water and [^99mTcO₄]⁻, even using arenes incompatible with Fischer–Hafner conditions. To unambiguously confirm the nature of these unprecedented ^99mTc complexes, their rhenium homologous have been prepared by substituting naphthalene ligands in [Re(η⁶-C₁₀H₈)₂]⁺ with the corresponding phenyl groups. The ease with which highly stable [^99mTc(η⁶-C₆R₆)₂]⁺ complexes are formed under standard labeling conditions enables a multitude of new potential imaging agents based on commercial pharmaceuticals or lead structures.     

Comparison of ‘classic’ Tc-DTPA, Tc(CO)3-DTPA and Tc(CO)2(NO)-DTPA

Diethylenetriamine pentaacetic acid (DTPA) was labeled with ^99mTc in three different ways, resulting in ‘classic’ ^99mTc-DTPA, ^99mTc(CO)₃-DTPA and ^99mTc(CO)₂(NO)-DTPA. The biodistribution of the formed DTPA-complexes was studied in mice with a special emphasis on the behavior of the novel tricarbonyl and dicarbonyl-nitrosyl complexes, which was clearly differing from that of ‘classic’ ^99mTc-DTPA. The conversion of a Tc-tricarbonyl complex to a Tc-dicarbonyl-nitrosyl complex using NO⁺ reagents offers a synthetic tool for preparing a novel class of ^99mTc labeled compounds.     

The case for fractional solubility profiles

This work reports the synthesis, radiolabeling and preliminary biodistribution results in tumor-bearing mice of [^99mTc(CO)₃(PA-TZ-CHC)]⁺. The novel colchicine (CHC) ligand was successfully synthesized via “click” reaction. Radiolabeling was performed in high yield with [^99mTc(CO)₃]⁺ core to get [^99mTc(CO)₃(PA-TZ-CHC)]⁺, which was hydrophilic and cationic, and was stable at room temperature. Biodistribution studies in tumor-bearing mice showed that [^99mTc(CO)₃(PA-TZ-CHC)]⁺ accumulated in the tumor with good uptake while comparatively low retention. The clearance of the ^99mTc-complex from normal organs was fast, resulting in increasing tumor/blood and tumor/muscle ratios. The promising results in preliminary biodistribution studies warrant further research to improve tumor targeting efficacy and pharmacokinetic profile of radiolabeled CHC derivative by structural modification.     

Preparation and biological evaluation of Tc-CO-MIBI as myocardial perfusion imaging agent

^99mTc-Sestamibi has been playing an important role in the cardiac imaging for the last decades. Previously, we reported that [^99mTc(CO)₃(MIBI)₃]⁺ demonstrated a significant location in myocardium with a lower liver uptake as compared with ^99mTc-Sestamibi. In this work, we found that new [^99mTc(CO)₂(MIBI)₄]⁺ could be prepared with high radiochemical purity. The inter-transformations between [^99mTc(CO)₃(H₂O)(MIBI)₂]⁺, [^99mTc(CO)₃(MIBI)₃]⁺, and [^99mTc(CO)₂(MIBI)₄]⁺ were investigated and biodistribution was performed to evaluate the [^99mTc(CO)₂(MIBI)₄]⁺ as a myocardial perfusion imaging agent. The results showed that one more CO was replaced by MIBI slowing down the pharmacokinetics. The structure characterization was performed on their corresponding rhenium complexes, and the results indicated that there were differences between ^99mTc-CO-MIBI and Re-CO-MIBI in preparation and hydrophobic characteristics.     

[M(CO)2(NO)], a new core in bioorganometallic chemistry: model complexes of [Re(CO)2(NO)] and [Tc(CO)2(NO)]

In this study selected bidentate (L²) and tridentate (L³) ligands were coordinated to the Re(I) or Tc(I) core [M(CO)₂(NO)]²⁺ resulting in complexes of the general formula fac-[MX(L²)(CO)₂(NO)] and fac-[M(L³)(CO)₂(NO)] (M = Re or Tc; X = Br or Cl). The complexes were obtained directly from the reaction of [M(CO)₂(NO)]²⁺ with the ligand or indirectly by first reacting the ligand with [M(CO)₃]⁺ and subsequent nitrosylation with [NO][BF₄] or [NO][HSO₄]. Most of the reactions were performed with cold rhenium on a macroscopic level before the conditions were adapted to the n.c.a. level with technetium (^99mTc). Chloride, bromide and nitrate were used as monodentate ligands, picolinic acid (PIC) as a bidentate ligand and histidine (HIS), iminodiacetic acid (IDA) and nitrilotriacetic acid (NTA) as tridentate ligands. We synthesised and describe the dinuclear complex [ReCl(μ-Cl)(CO)₂(NO)]₂ and the mononuclear complexes [NEt₄][ReCl₃(CO)₂(NO)], [NEt₄][ReBr₃(CO)₂(NO)], [ReBr(PIC)(CO)₂(NO)], [NMe₄][Re(NO₃)₃(CO)₂(NO)], [Re(HIS)(CO)₂(NO)][BF₄], [⁹⁹Tc(HIS)(CO)₂(NO)][BF₄], [^99mTc(IDA)(CO)₂ (NO)] and [^99mTc(NTA)(CO)₂(NO)]. The chemical and physical characteristics of the Re and Tc-dicarbonyl-nitrosyl complexes differ significantly from those of the corresponding tricarbonyl compounds.     

To Sandwich Technetium: Highly Functionalized Bis‐Arene Complexes [99mTc(η6‐arene)2]+ Directly from Water and [99mTcO4]−

The labeling of (bio)molecules with metallic radionuclides such as ^99mTc demands conjugated, multidentate chelators. However, this is not always necessary since phenyl rings can directly serve as integrated, organometallic ligands. Bis‐arene sandwich complexes are generally prepared by the Fischer–Hafner reaction. In extension of this, we show that [^99mTc(η⁶‐C₆R₆)₂]⁺‐type complexes are directly accessible from water and [^99mTcO₄]^?, even using arenes incompatible with Fischer–Hafner conditions. To unambiguously confirm the nature of these unprecedented ^99mTc complexes, their rhenium homologous have been prepared by substituting naphthalene ligands in [Re(η⁶‐C₁₀H₈)₂]⁺ with the corresponding phenyl groups. The ease with which highly stable [^99mTc(η⁶‐C₆R₆)₂]⁺ complexes are formed under standard labeling conditions enables a multitude of new potential imaging agents based on commercial pharmaceuticals or lead structures.