Octahedral Hexanuclear Rhenium Cluster Dimers Bridged by Pyrazine or 4,4'-Bipyridine with 23- and 24-Electron Configurations.

New pyrazine (pz)- and 4,4'-bipyridine (4,4'-bpy)-bridged octahedral hexanuclear rhenium(III) cluster dimers, [{Re6(µ3-S)8Cl5}2(µ-L)]6- (L = pz, [1]6-; L = 4,4'-bpy, [2]6-), with 2 × 24 d-electrons {Re6(24e)}2 were obtained in a single-step reaction via photoirradiation of [Re6(µ3-S)8Cl6]4- with L in a 2:1 ratio at room temperature. The {Re6(23e)}2 dimers, [{Re6(µ3-S)8Cl5}2(µ-L)]4- (L = pz, [1']4-; L = 4,4'-bpy, [2']4-), were synthesized through two-electron oxidation of [1]6- and [2]6-, respectively. The single-crystal X-ray structures of [1]6- and [1']4- were determined, revealing structural distortion of the Re6 core of [1']4- due to the Jahn-Teller effect. The cyclic voltammograms of [1]6- and [2]6- showed two steps of one-electron redox processes attributable to Re6(23e)Re6(24e)/{Re6(24e)}2 and {Re6(23e)}2/Re6(23e)Re6(24e), respectively. The separation between the two redox potentials is small (0.056 V for [1]6- and 0.039 V for [2]6-). The magnetic susceptibilities of [1']4- and [2']4- were almost temperature-independent, with values of 2.98 and 2.85 µB, respectively, indicating paramagnetism. These results suggest weak electronic interaction between two cluster units bridged by pz or 4,4'-bpy in the intercluster mixed valence state. The compounds [1]6- and [2]6- show photoluminescence in the near-infrared region at 296 K in the solid state.

Luminescence Color and Intensity Changes of Nitridorhenium(V) Complexes Induced by Protonation/Deprotonation on the Bidentate Azolylpyridine Ligands.

Tricyanidonitridorhenium(V) complexes with azolylpyridines, namely, [ReN(CN)3(H-N2py)]- (1-H, H-N2py = 2-(3-pyrazolyl)pyridine) and [ReN(CN)3(L)]2- (2-a, L = 2-[1,2,3]-triazol-4-yl-pyridine anion (N3py-), and 3-a, that is, L = 2-(tetrazol-5-yl)-pyridine anion (N4py-)), were newly synthesized and characterized. The structures of the new complexes were determined by single-crystal X-ray analysis. The 1-H complex includes two geometrical isomers in which an isomer is the conformation with the pyridyl (py) and pyrazolyl (pyrz) moieties of H-N2py occupying the trans site to the nitrido (the ax site) and the trans site to the cyanido (the eq site), respectively, in a bidentate fashion; the other isomer is the py and pyrz moieties coordinated to the eq and ax sites. In 2-a and 3-a, the triazolyl (trz) and tetrazoly (tetrz) moieties in N3py- and N4py- occupy the eq site, and the py moieties in N3py- and N4py- coordinate to the ax site. The complex 1-H is deprotonated upon the addition of 1,8-diazabicyclo[5.4.0]undec-7-one or NaOH to produce [ReN(CN)3(N2py)]2- (1-a), and 2-a is protonated upon the addition of p-toluene sulfonic acid (TsOH) to give [ReN(CN)3(H-N3py)]- (2-H) in DMSO. The protonation reaction does not occur for 3-a with TsOH in DMSO. All the complexes show one-electron redox waves of the Re(VI)/Re(V) and azolylpyridine ligand-centered processes in 0.1 M (n-C4H9)4NPF6-DMSO. All the complexes exhibit photoluminescence in DMSO and in the crystalline phase at 296 K. The emissive excited states of the complexes in DMSO were assigned to MLCT with a spin triplet nature. The emission band shifts to shorter and longer wavelengths upon protonation and deprotonation of the coordinated azolylpyridines, respectively. The emission color and intensity changes of 2-H and 2-a in the presence of acidic and basic vapors were investigated.

Fibroblast activation protein targeted therapy using [177Lu]FAPI-46 compared with [225Ac]FAPI-46 in a pancreatic cancer model.

PURPOSE: Fibroblast activation protein (FAP), which has high expression in cancer-associated fibroblasts of epithelial cancers, can be used as a theranostic target. Our previous study used 64Cu and 225Ac-labelled FAP inhibitors (FAPI-04) for a FAP-expressing pancreatic cancer xenograft imaging and therapy. However, the optimal therapeutic radionuclide for FAPI needs to be investigated further. In this study, we evaluated the therapeutic effects of beta-emitter (177Lu)-labelled FAPI-46 and alpha-emitter (225Ac)-labelled FAPI-46 in pancreatic cancer models. METHODS: PET scans (1 h post injection) were acquired in PANC-1 xenograft mice (n = 9) after the administration of [18F]FAPI-74 (12.4 ± 1.7 MBq) for the companion imaging. The biodistribution of [177Lu]FAPI-46 and [225Ac]FAPI-46 were evaluated in the xenograft model (total n = 12). For the determination of treatment effects, [177Lu]FAPI-46 and [225Ac]FAPI-46 were injected into PANC-1 xenograft mice at different doses: 3 MBq (n = 6), 10 MBq (n = 6), 30 MBq (n = 6), control (n = 4) for [177Lu]FAPI-46, and 3 kBq (n = 3), 10 kBq (n = 2), 30 kBq (n = 6), control (n = 7) for [225Ac]FAPI-46. Tumour sizes and body weights were followed. RESULTS: [18F]FAPI-74 showed rapid clearance by the kidneys and high accumulation in the tumour and intestine 1 h after administration. [177Lu]FAPI-46 and [225Ac]FAPI-46 also showed rapid clearance by the kidneys and relatively high accumulation in the tumour at 3 h. Both [177Lu]FAPI-46 and [225Ac]FAPI-46 showed tumour-suppressive effects, with a mild decrease in body weight. The treatment effects of [177Lu]FAPI-46 were relatively slow but lasted longer than those of [225Ac]FAPI-46. CONCLUSION: This study suggested the possible application of FAPI radioligand therapy in FAP-expressing pancreatic cancer. Further evaluation is necessary to find the best radionuclide with shorter half-life, as well as the combination with therapies targeting tumour cells directly.

Synthesis, Structures, and Photoluminescent Properties of Tricyanidonitridorhenium(V) Complexes with Bipyridine-Type Ligands.

Tricyanidonitridorhenium(V) complexes with 2,2'-bipyridine (bpy) derivatives in which the 4 and 4' positions were substituted by X, [ReN(CN)3(X2bpy)]- (X = NMe2, NH2, OMe, Me, Cl, and Br), were newly synthesized and characterized. The structures of the new complexes were determined by single-crystal X-ray analysis. UV-vis spectra of the complexes in dimethyl sulfoxide (DMSO) showed that the peak maximum wavelengths of rhenium-to-π* bpy-type-ligand charge transfer were in the range of 474-542 nm. Cyclic voltammograms in n-(C4H9)4NPF6-DMSO showed one-electron oxidation and reduction waves corresponding to the Re(VI/V) and X2bpy0/- processes, respectively. The new complexes and [ReN(CN)3bpy]- showed photoluminescence in the crystalline phase at 295 and 80 K and in DMSO at 295 K. The origin of the emission in DMSO was attributed to the triplet nature of the rhenium-to-π* bpy-type-ligand charge-transfer transition. Density functional theory calculations showed that the highest occupied and lowest unoccupied molecular orbitals were primarily localized on the dxy orbital of the rhenium and π* orbitals of the bpy-type ligand, respectively.

Molecular geochemistry of radium: A key to understanding cation adsorption reaction on clay minerals.

Adsorption reactions of various cations on clay minerals have different effects on their environmental behaviors depending on the molecular-scale adsorption structure. Some cations form outer-sphere complexes via hydration, while others create inner-sphere complexes through dehydration. This preference dictates their environmental impact. However, the factors controlling these complex formations remain unclear. Furthermore, research on the adsorption preferences of radium (Ra) is lacking. Thus, this study conducted the first EXAFS study of Ra2+ adsorbed on clay minerals and showed that Ra2+ forms inner-sphere complexes on vermiculite, which can be surprising because Ra2+ is a divalent cation and prefers to be hydrated. In order to investigate the factors controlling the complex formations, this study conducted systematic EXAFS measurements and DFT calculations for alkali and alkaline earth metal cations. The results showed the importance of the size-matching effect between the adsorbed cation and the cavity of the tetrahedral sheets and that the complex formation can be estimated by the combination of the ionic radius and hydration enthalpy of the adsorbed cation. Furthermore, this study also analyzed environmental core samples. Their results showed the fixation of Ra2+ by clay minerals and the controlling factors can effectively predict cation environmental behavior.

Tuning the Ground- and Excited-State Redox Potentials of Octahedral Hexanuclear Rhenium(III) Complexes by the Combination of Terminal Halide and N-Heteroaromatic Ligands.

The present study reports that the ground- and excited-state Re6(23e)/Re6(24e) redox potentials of an octahedral hexanuclear rhenium(III) complex can be controlled by systematically changing the number and type of the N-heteroaromatic ligand (L) and the number of chloride ions at the six terminal positions. Photoirradiation of [Re6(µ3-S)8Cl6]4- with an excess amount of L afforded a mono-L-substituted hexanuclear rhenium(III) complex, [Re6(µ3-S)8Cl5(L)]3- (L = 4-dimethylaminopyridine (dmap), 3,5-lutidine (lut), 4-methylpyridine (mpy), pyridine (py), 4,4'-bipyridine (bpy), 4-cyanopyridine (cpy), and pyrazine (pz)). The bis- and tris-lut-substituted complexes, trans- and cis-[Re6(µ3-S)8Cl4(lut)2]2- and mer-[Re6(µ3-S)8Cl3(lut)3]-, were synthesized by the reaction of [Re6(µ3-S)8Cl6]3- with an excess amount of lut in refluxed N,N-dimethylformamide. The mono-L-substituted complexes showed one-electron redox processes assignable to E 1/2[Re6(23e)/Re6(24e)] = 0.49-0.58 V versus Ag/AgCl. The ground-state oxidation potentials were linearly correlated with the pK a of the N-heteroaromatic ligand [pK a(L)], the 1H NMR chemical shift of the ortho proton on the coordinating ligand, and the Hammett constant (σ) of the pyridyl-ligand substituent. The series of [Re6(µ3-S)8X6-n (L) n ] n-4 complexes (n = 0, X = Cl, Br, I, or NCS; n = 1-3, X = Cl) showed a linear correlation with the sum of the Lever electrochemical parameters at the six terminal ligands (ΣE L). The cyclic voltammograms of the mono-L-substituted complexes (L = bpy, cpy, and pz) showed one-electron redox waves assignable to E 1/2(L0/L-) = -1.28 to -1.48 V versus Ag/AgCl. Two types of photoluminescences were observed for the complexes, originating from the cluster core-centered excited triplet state (3CC) for L = dmap, lut, mpy, and py and from the metal-to-ligand charge-transfer excited triplet state (3MLCT) for L = bpy, cpy, and pz. The complexes with the 3CC character exhibited emission features and photophysical properties similar to those of ordinary hexanuclear rhenium complexes. The emission maximum wavelength of the complexes with 3MLCT shifted to the longer wavelength in the order L = 4-phenylpyridine (ppy), bpy, pz, and cpy, which agreed with the difference between E 1/2[Re6(23e)/Re6(24e)] and E 1/2(L0/L-). The calculated oxidation potential of the excited hexanuclear rhenium complex with the 3CC character was linearly correlated with pK a(L), σ, and ΣE L. The ground- and excited-state oxidation potentials were finely tuned by the combination of halide and L ligands at the terminal positions.

Extended X-ray absorption fine structure spectroscopy measurements and ab initio molecular dynamics simulations reveal the hydration structure of the radium(II) ion.

Radium is refocused from the viewpoint of an environmental pollutant and cancer therapy using alpha particles, where it mainly exists as a hydrated ion. We investigated the radium hydration structure and the dynamics of water molecules by extended X-ray absorption fine structure (EXAFS) spectroscopy and ab initio molecular dynamics (AIMD) simulation. The EXAFS experiment showed that the coordination number and average distance between radium ion and the oxygen atoms in the first hydration shell are 9.2 ± 1.9 and 2.87 ± 0.06 Å, respectively. They are consistent with those obtained from the AIMD simulations, 8.4 and 2.88 Å. The AIMD simulations also revealed that the water molecules in the first hydration shell of radium are less structured and more mobile than those of barium, which is an analogous element of radium. Our results indicate that radium can be more labile than barium in terms of interactions with water.

Theranostics Targeting Fibroblast Activation Protein in the Tumor Stroma: 64Cu- and 225Ac-Labeled FAPI-04 in Pancreatic Cancer Xenograft Mouse Models.

Fibroblast activation protein (FAP), which promotes tumor growth and progression, is overexpressed in cancer-associated fibroblasts of many human epithelial cancers. Because of its low expression in normal organs, FAP is an excellent target for theranostics. In this study, we used radionuclides with relatively long half-lives, 64Cu (half-life, 12.7 h) and 225Ac (half-life, 10 d), to label FAP inhibitors (FAPIs) in mice with human pancreatic cancer xenografts. Methods: Male nude mice (body weight, 22.5 ± 1.2 g) were subcutaneously injected with human pancreatic cancer cells (PANC-1, n = 12; MIA PaCa-2, n = 8). Tumor xenograft mice were investigated after the intravenous injection of 64Cu-FAPI-04 (7.21 ± 0.46 MBq) by dynamic and delayed PET scans (2.5 h after injection). Static scans 1 h after the injection of 68Ga-FAPI-04 (3.6 ± 1.4 MBq) were also acquired for comparisons using the same cohort of mice (n = 8). Immunohistochemical staining was performed to confirm FAP expression in tumor xenografts using an FAP-α-antibody. For radioligand therapy, 225Ac-FAPI-04 (34 kBq) was injected into PANC-1 xenograft mice (n = 6). Tumor size was monitored and compared with that of control mice (n = 6). Results: Dynamic imaging of 64Cu-FAPI-04 showed rapid clearance through the kidneys and slow washout from tumors. Delayed PET imaging of 64Cu-FAPI-04 showed mild uptake in tumors and relatively high uptake in the liver and intestine. Accumulation levels in the tumor or normal organs were significantly higher for 64Cu-FAPI-04 than for 68Ga-FAPI-04, except in the heart, and excretion in the urine was higher for 68Ga-FAPI-04 than for 64Cu-FAPI-04. Immunohistochemical staining revealed abundant FAP expression in the stroma of xenografts. 225Ac-FAPI-04 injection showed significant tumor growth suppression in the PANC-1 xenograft mice, compared with the control mice, without a significant change in body weight. Conclusion: This proof-of-concept study showed that 64Cu-FAPI-04 and 225Ac-FAPI-04 could be used in theranostics for the treatment of FAP-expressing pancreatic cancer. α-therapy targeting FAP in the cancer stroma is effective and will contribute to the development of a new treatment strategy.

Synthesis, structures, redox properties, and theoretical calculations of thiohalide capped octahedral hexanuclear technetium(iii) clusters.

The first thiohalide µ3-capped octahedral hexanuclear technetium clusters with 24 valence electrons, [Tc6(µ3-S)8-n(µ3-Br)nBr6]n-4 [n = 1 ([Tc-S7Br]3-) and n = 2 ([Tc-S6Br2]2-)] and [Tc6(µ3-S)7(µ3-Cl)Cl6]3- ([Tc-S7Cl]3-), were synthesized and characterized. The structures of [Tc-S7Br]3-, [Tc-S6Br2]2-, and [Tc-S7Cl]3- were determined by single-crystal X-ray analysis. The Tc-Tc bond distances in [Tc-S7Br]3-, [Tc-S6Br2]2-, and [Tc-S7Cl]3- are 2.5842(6)-2.6029(6) Å (avg. 2.593(2) Å), 2.5835(10)-2.6049(10) Å (avg. 2.596(1) Å), and 2.5829(4)-2.5940(4) Å (avg. 2.587(3) Å), respectively. The capping halide and sulfide ligands in [Tc-S7Br]3-, [Tc-S6Br2]2-, and [Tc-S7Cl]3- were disordered in the crystals. The bond distances of Tc-S/Br as a function of the occupancies of the capping bromides for [Tc-S6Br2]2-, [Tc-S7Br]3-, and [Tc6(µ3-S)8Br6]4- ([Tc-S8]4-) showed a linear correlation. The one-electron reduction waves assignable to the Tc/TcIITc [Tc6(24e/25e)] process were observed for the novel complexes. Density functional theory (DFT) calculations of the hexanuclear technetium complexes showed a smaller energy gap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of the hexanuclear technetium complexes compared to those of the rhenium analogues. The electronic transitions of the new technetium complexes shifted to lower energy compared to the isotypic rhenium complexes.

Synthesis and Photoluminescence of Tetracyanidonitridorhenium(V) Complexes with Five-Membered N-Heteroaromatic Ligands and Photoluminescence-Intensity Change.

Novel tetracyanidonitridorhenium(V) complexes with five-membered N-heteroaromatic ligands, (PPh4)2[ReN(CN)4L] [L = imidazole (Him) (2), 1-methylimidazole (Mim) (3), and pyrazole (pyz) (4)] and (PPh4)2[ReN(CN)4L]·L [L = Him (5) and Mim (6)], were synthesized by the reactions of (PPh4)2[ReN(CN)4] (1) with Him, Mim, and pyz, and their structures were determined by single-crystal X-ray analysis. The complexes 2, 3, 4, and 6 showed intense photoluminescence, with the emission quantum yields (Φem) being 0.65-0.75 in the solid state at 296 K. In contrast, the Φem and τem values of 5 are significantly smaller and shorter, respectively, than the relevant values of 2. The interconversion reactions among 1, 2, and 5 accompanied by large photoluminescence-intensity changes were accomplished by solvent-free reactions and exposure of water. The mechanochemical reaction of 2 with 1 mol equiv of Him in the solid state gave 5. Complex 5 was also obtained by the mechanochemical reaction of 1 with 2 mol equivalents of Him in the solid state. By placing solid of 5 in water, the solid showed intense photoluminescence to give 2. Complex 1 was produced under vacuum at 185 °C from 2 or 5.

A luminescent dicyanidonitridotechnetium(v) core with tridentate ligand coordination sites.

A novel, luminescent technetium complex, [TcN(CN)2bpa] (bpa = bis-(2-pyridylmethyl)amine), with tridentate ligand coordination sites was synthesized and characterized. Photoemission with a maximum wavelength at 666 nm was observed in the solid-state at 296 K.