Rhenium and Technetium Tricarbonyl Complexes of N‑Heterocyclic Carbene Ligands

A strategy for the conjugation of N-heterocyclic carbene (NHC) ligands to biomolecules via amide bond formation is described. Both 1-(2-pyridyl)­imidazolium or 1-(2-pyridyl)­benzimidazolium salts functionalized with a pendant carboxylic acid group were prepared and coupled to glycine benzyl ester using 1-ethyl-3-(3-(dimethylamino)­propyl)­carbodiimide. A series of 10 rhenium­(I) tricarbonyl complexes of the form [ReX­(CO)₃(ĈN)] (ĈN is a bidentate NHC ligand, and X is a monodentate anionic ligand: Cl^–, RCO₂^–) were synthesized via a Ag₂O transmetalation protocol from the Re­(I) precursor compound Re­(CO)₅Cl. The synthesized azolium salts and Re­(I) complexes were characterized by elemental analysis and by ¹H and ¹³C NMR spectroscopy, and the molecular structures for one imidazolium salt and seven Re­(I) complexes were determined by single-crystal X-ray diffraction. ¹H NMR and mass spectrometry studies for an acetonitrile-<i>d</i>₃ solution of [ReCl­(CO)₃(1-(2-pyridyl)-3-methylimidazolylidene)] show that the monodentate chloride ligand is labile and exchanges with this solvent yielding a cationic acetonitrile adduct. For the first time the labeling of an NHC ligand with technetium-99m is reported. Rapid Tc-99m labeling was achieved by heating the imidazolium salt 1-(2-pyridyl)-3-methylimidazolium iodide and Ag₂O in methanol, followed by the addition of <i>fac</i>-[^99mTc­(OH₂)₃(CO)₃]⁺. To confirm the structure of the ^99mTc-labeled complex, the equivalent ⁹⁹Tc complex was prepared, and mass spectrometric studies showed that the formed Tc complexes are of the form [^{99<i>m</i>/99}Tc­(CH₃CN)­(CO)₃(1-(2-pyridyl)-3-methylimidazolylidene)]⁺ with an acetonitrile molecule coordinated to the metal center

Triamidetriamine Bearing Macrobicyclic and Macrotricyclic Ligands: Potential Applications in the Development of Copper-64 Radiopharmaceuticals

A versatile and straightforward synthetic approach is described for the preparation of triamide bearing analogues of sarcophagine hexaazamacrobicyclic cage ligands without the need for a templating metal ion. Reaction of 1,1,1-<i>tris</i>(aminoethyl)­ethane (tame) with 3 equiv of 2-chloroacetyl chloride, yields the <i>tris</i>(α-chloroamide) synthetic intermediate <b>6</b>, which when treated with either 1,1,1-<i>tris</i>(aminoethyl)­ethane or 1,4,7-triazacyclononane furnished two novel triamidetriamine cryptand ligands (<b>7</b> and <b>8</b> respectively). The Co­(III) and Cu­(II) complexes of cryptand <b>7</b> were prepared; however, cryptand <b>8</b> could not be metalated. The cryptands and the Co­(III) complex <b>9</b> have been characterized by elemental analysis, ¹H and ¹³C NMR spectroscopy, and X-ray crystallography. These studies confirm that the Co­(III) complex <b>9</b> adopts an octahedral geometry with three facial deprotonated amido-donors and three facial amine donor groups. The Cu­(II) complex <b>10</b> was characterized by elemental analysis, single crystal X-ray crystallography, cyclic voltammetry, and UV–visible absorption spectroscopy. In contrast to the Co­(III) complex (<b>9</b>), the Cu­(II) center adopts a square planar coordination geometry, with two amine and two deprotonated amido donor groups. Compound <b>10</b> exhibited a quasi-reversible, one-electron oxidation, which is assigned to the Cu^2+/3+ redox couple. These cryptands represent interesting ligands for radiopharmaceutical applications, and <b>7</b> has been labeled with ⁶⁴Cu to give ⁶⁴Cu-<b>10</b>. This complex showed good stability when subjected to l-cysteine challenge whereas low levels of decomplexation were evident in the presence of l-histidine

Synthesis and in Vivo Biological Evaluation of ⁶⁸Ga-Labeled Carbonic Anhydrase IX Targeting Small Molecules for Positron Emission Tomography

Tumor hypoxia contributes resistance to chemo- and radiotherapy, while oxygenated tumors are sensitive to these treatments. The indirect detection of hypoxic tumors is possible by targeting carbonic anhydrase IX (CA IX), an enzyme overexpressed in hypoxic tumors, with sulfonamide-based imaging agents. In this study, we present the design and synthesis of novel gallium-radiolabeled small-molecule sulfonamides targeting CA IX. The compounds display favorable in vivo pharmacokinetics and stability. We demonstrate that our lead compound, [⁶⁸Ga]-<b>2</b>, discriminates CA IX-expressing tumors in vivo in a mouse xenograft model using positron emission tomography (PET). This compound shows specific tumor accumulation and low uptake in blood and clears intact to the urine. These findings were reproduced in a second study using PET/computed tomography. Small molecules investigated to date utilizing ⁶⁸Ga for preclinical CA IX imaging are scarce, and this is one of the first effective ⁶⁸Ga compounds reported for PET imaging of CA IX