Tuning the Softness of the Pendant Arms and the Polyazamacrocyclic Backbone to Chelate the 203Pb/212Pb Theranostic Pair.

A series of macrocyclic ligands were considered for the chelation of Pb2+: 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-10-acetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), 1,7-bis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane-4,10-diacetic acid (DO2A2S), 1,5,9-tris[2-(methylsulfanyl)ethyl]-1,5,9-triazacyclododecane (TACD3S), 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetrazacyclotridecane (TRI4S), and 1,4,8,11-tetrakis[2-(methylsulfanyl)ethyl]-1,4,8,11-tetrazacyclotetradecane (TE4S). The equilibrium, the acid-mediated dissociation kinetics, and the structural properties of the Pb2+ complexes formed by these chelators were examined by UV-Visible and nuclear magnetic resonance (NMR) spectroscopies, combined with potentiometry and density functional theory (DFT) calculations. The obtained results indicated that DO4S, DO3S, DO3SAm, and DO2A2S were able to efficiently chelate Pb2+ and that the most suitable macrocyclic scaffold for Pb2+ is 1,4,7,10-tetrazacyclododecane. NMR spectroscopy gave insights into the solution structures of the Pb2+ complexes, and 1H-207Pb interactions confirmed the involvement of S and/or O donors in the metal coordination sphere. Highly fluxional solution behavior was discovered when Pb2+ was coordinated to symmetric ligands (i.e., DO4S and DO2A2S) while the introduction of structural asymmetry in DO3S and DO3SAm slowed down the intramolecular dynamics. The ligand ability to chelate [203Pb]Pb2+ under highly dilute reaction conditions was explored through radiolabeling experiments. While DO4S and DO3S possessed modest performance, DO3SAm and DO2A2S demonstrated high complexation efficiency under mild reaction conditions (pH = 7, 5 min reaction time). The [203Pb]Pb2+ complexes' integrity in human serum over 24 h was appreciably good for [203Pb][Pb(DO4S)]2+ (80 ± 5%) and excellent for [203Pb][Pb(DO3SAm)]2+ (93 ± 1%) and [203Pb][Pb(DO2A2S)] (94 ± 1%). These results reveal the promise of DO2A2S and DO3SAm as chelators in cutting-edge theranostic [203/212Pb]Pb2+ radiopharmaceuticals.

Capturing Mercury-197m/g for Auger Electron Therapy and Cancer Theranostic with Sulfur-Containing Cyclen-Based Macrocycles.

The interest in mercury radioisotopes, 197mHg (t1/2 = 23.8 h) and 197gHg (t1/2 = 64.14 h), has recently been reignited by the dual diagnostic and therapeutic nature of their nuclear decays. These isotopes emit γ-rays suitable for single photon emission computed tomography imaging and Auger electrons which can be exploited for treating small and metastatic tumors. However, the clinical utilization of 197m/gHg radionuclides is obstructed by the lack of chelators capable of securely binding them to tumor-seeking vectors. This work aims to address this challenge by investigating a series of chemically tailored macrocyclic platforms with sulfur-containing side arms, namely, 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO3S), and 1,7-bis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane-4,10-diacetic acid (DO2A2S). 1,4,7,10-Tetrazacyclododecane-1,4,7,10-tetracetic acid (DOTA), the widest explored chelator in nuclear medicine, and the nonfunctionalized backbone 1,4,7,10-tetrazacyclododecane (cyclen) were considered as well to shed light on the role of the sulfanyl arms in the metal coordination. To this purpose, a comprehensive experimental and theoretical study encompassing aqueous coordination chemistry investigations through potentiometry, nuclear magnetic resonance (NMR) spectroscopy, X-ray crystallography, and density functional theory (DFT) calculations, as well as concentration- and temperature-dependent [197m/gHg]Hg2+ radiolabeling and in vitro stability assays in human serum was conducted. The obtained results reveal that the investigated chelators rapidly complex Hg2+ in aqueous media, forming extremely thermodynamically stable 1:1 metal-to-ligand complexes with superior stabilities compared to those of DOTA or cyclen. These complexes exhibited 6- to 8-fold coordination environments, with donors statically bound to the metal center, as evidenced by the presence of 1H-199Hg spin-spin coupling via NMR. A similar octacoordinated environment was also found for DOTA in both solution and solid state, but in this case, multiple slowly exchanging conformers were detected at ambient temperature. The sulfur-rich ligands quantitatively incorporate cyclotron-produced [197m/gHg]Hg2+ under relatively mild reaction conditions (pH = 7 and T = 50 °C), with the resulting radioactive complexes exhibiting decent stability in human serum (up to 75% after 24 h). By developing viable chelators and understanding the impact of structural modifications, our research addresses the scarcity of suitable chelating agents for 197m/gHg, offering promise for its future in vivo application as a theranostic Auger-emitter radiometal.

Selective Chelation of the Exotic Meitner-Auger Emitter Mercury-197 m/g with Sulfur-Rich Macrocyclic Ligands: Towards the Future of Theranostic Radiopharmaceuticals.

Mercury-197 m/g are a promising pair of radioactive isomers for incorporation into a theranostic as they can be used as a diagnostic agent using SPECT imaging and a therapeutic via Meitner-Auger electron emissions. However, the current absence of ligands able to stably coordinate 197m/g Hg to a tumour-targeting vector precludes their use in vivo. To address this, we report herein a series of sulfur-rich chelators capable of incorporating 197m/g Hg into a radiopharmaceutical. 1,4,7,10-Tetrathia-13-azacyclopentadecane (NS4 ) and its derivatives, (2-(1,4,7,10-tetrathia-13-azacyclopentadecan-13-yl)acetic acid (NS4 -CA) and N-benzyl-2-(1,4,7,10-tetrathia-13-azacyclopentadecan-13-yl)acetamide (NS4 -BA), were designed, synthesized and analyzed for their ability to coordinate Hg2+ through a combination of theoretical (DFT) and experimental coordination chemistry studies (NMR and mass spectrometry) as well as 197m/g Hg radiolabeling studies and in vitro stability assays. The development of stable ligands for 197m/g Hg reported herein is extremely impactful as it would enable their use for in vivo imaging and therapy, leading to personalized treatments for cancer.

Is Smaller Better? Cu2+/Cu+ Coordination Chemistry and Copper-64 Radiochemical Investigation of a 1,4,7-Triazacyclononane-Based Sulfur-Rich Chelator.

The biologically triggered reduction of Cu2+ to Cu+ has been postulated as a possible in vivo decomplexation pathway in 64/67Cu-based radiopharmaceuticals. In an attempt to hinder this phenomenon, we have previously developed a family of S-containing polyazamacrocycles based on 12-, 13-, or 14-membered tetraaza rings able to stabilize both oxidation states. However, despite the high thermodynamic stability of the resulting Cu2+/+ complexes, a marked [64Cu]Cu2+ release was detected in human serum, likely as a result of the partially saturated coordination sphere around the copper center. In the present work, a new hexadentate macrocyclic ligand, 1,4,7-tris[2-(methylsulfanyl)ethyl)]-1,4,7-triazacyclononane (NO3S), was synthesized by hypothesizing that a smaller macrocyclic backbone could thwart the observed demetalation by fully encapsulating the copper ion. To unveil the role of the S donors in the metal binding, the corresponding alkyl analogue 1,4,7-tris-n-butyl-1,4,7-triazacyclononane (TACN-n-Bu) was considered as comparison. The acid-base properties of the free ligands and the kinetic, thermodynamic, and structural properties of their Cu2+ and Cu+ complexes were investigated in solution and solid (crystal) states through a combination of spectroscopic and electrochemical techniques. The formation of two stable mononuclear species was detected in aqueous solution for both ligands. The pCu2+ value for NO3S at physiological pH was 6 orders of magnitude higher than that computed for TACN-n-Bu, pointing out the significant stabilizing contribution arising from the Cu2+-S interactions. In both the solid state and solution, Cu2+ was fully embedded in the ligand cleft in a hexacoordinated N3S3 environment. Furthermore, NO3S exhibited a remarkable ability to form a stable complex with Cu+ through the involvement of all of the donors in the coordination sphere. Radiolabeling studies evidenced an excellent affinity of NO3S toward [64Cu]Cu2+, as quantitative incorporation was achieved at high apparent molar activity (∼10 MBq/nmol) and under mild conditions (ambient temperature, neutral pH, 10 min reaction time). Human serum stability assays revealed an increased stability of [64Cu][Cu(NO3S)]2+ when compared to the corresponding complexes formed by 12-, 13-, or 14-membered tetraaza rings.

Tuning the Framework of Thioether-Functionalized Polyazamacrocycles: Searching for a Chelator for Theranostic Silver Radioisotopes.

Silver-111 is an attractive unconventional candidate for targeted cancer therapy as well as for single photon emission computed tomography and can be complemented by silver-103 for positron emission tomography noninvasive diagnostic procedures. However, the shortage of chelating agents capable of forming stable complexes tethered to tumor-seeking vectors has hindered their in vivo application so far. In this study, a comparative investigation of a series of sulfur-containing structural homologues, namely, 1,4,7-tris[2-(methylsulfanyl)ethyl)]-1,4,7-triazacyclononane (NO3S), 1,5,9-tris[2-(methylsulfanyl)ethyl]-1,5,9-triazacyclododecane (TACD3S), 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclotridecane (TRI4S), and 1,4,8,11-tetrakis[2-(methylsulfanyl)ethyl]-1,4,8,11-tetraazacyclotetradecane (TE4S) was conducted to appraise the influence of different polyazamacrocyclic backbones on Ag+ complexation. The performances of these macrocycles were also compared with those of the previously reported Ag+/[111Ag]Ag+-chelator 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S). Nuclear magnetic resonance data supported by density functional theory calculations and X-ray crystallographic results gave insights into the coordination environment of these complexes, suggesting that all of the donor atoms are generally involved in the metal coordination. However, the modifications of the macrocycle topology alter the dynamic binding of the pendant arms or the conformation of the ring around the metal center. Combined pH/pAg-potentiometric and spectroscopic experiments revealed that the 12-member N4 backbone of DO4S forms the most stable Ag+ complex while both the enlargement and the shrinkage of the macrocyclic frame dwindle the stability of the complexes. Radiolabeling experiments, conducted with reactor-produced [111Ag]Ag+, evidenced that the thermodynamic stability trend is reflected in the ligand's ability to incorporate the radioactive ion at high molar activity, even in the presence of a competing cation (Pd2+), as well as in the integrity of the corresponding complexes in human serum. As a consequence, DO4S proved to be the most favorable candidate for future in vivo applications.

Chelation of Theranostic Copper Radioisotopes with S-Rich Macrocycles: From Radiolabelling of Copper-64 to In Vivo Investigation.

Copper radioisotopes are generally employed for cancer imaging and therapy when firmly coordinated via a chelating agent coupled to a tumor-seeking vector. However, the biologically triggered Cu2+-Cu+ redox switching may constrain the in vivo integrity of the resulting complex, leading to demetallation processes. This unsought pathway is expected to be hindered by chelators bearing N, O, and S donors which appropriately complements the borderline-hard and soft nature of Cu2+ and Cu+. In this work, the labelling performances of a series of S-rich polyazamacrocyclic chelators with [64Cu]Cu2+ and the stability of the [64Cu]Cu-complexes thereof were evaluated. Among the chelators considered, the best results were obtained with 1,7-bis [2-(methylsulfanyl)ethyl]-4,10,diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S). DO2A2S was labelled at high molar activities in mild reaction conditions, and its [64Cu]Cu2+ complex showed excellent integrity in human serum over 24 h. Biodistribution studies in BALB/c nude mice performed with [64Cu][Cu(DO2A2S)] revealed a behavior similar to other [64Cu]Cu-labelled cyclen derivatives characterized by high liver and kidney uptake, which could either be ascribed to transchelation phenomena or metabolic processing of the intact complex.

Copper Coordination Chemistry of Sulfur Pendant Cyclen Derivatives: An Attempt to Hinder the Reductive-Induced Demetalation in 64/67Cu Radiopharmaceuticals.

The Cu2+ complexes formed by a series of cyclen derivatives bearing sulfur pendant arms, 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-10-acetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), and 1,7-bis[2-(methylsulfanyl)ethyl]-4,10-diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S), were studied in aqueous solution at 25 °C from thermodynamic and structural points of view to evaluate their potential as chelators for copper radioisotopes. UV-vis spectrophotometric out-of-cell titrations under strongly acidic conditions, direct in-cell UV-vis titrations, potentiometric measurements at pH >4, and spectrophotometric Ag+-Cu2+ competition experiments were performed to evaluate the stoichiometry and stability constants of the Cu2+ complexes. A highly stable 1:1 metal-to-ligand complex (CuL) was found in solution at all pH values for all chelators, and for DO2A2S, protonated species were also detected under acidic conditions. The structures of the Cu2+ complexes in aqueous solution were investigated by UV-vis and electron paramagnetic resonance (EPR), and the results were supported by relativistic density functional theory (DFT) calculations. Isomers were detected that differed from their coordination modes. Crystals of [Cu(DO4S)(NO3)]·NO3 and [Cu(DO2A2S)] suitable for X-ray diffraction were obtained. Cyclic voltammetry (CV) experiments highlighted the remarkable stability of the copper complexes with reference to dissociation upon reduction from Cu2+ to Cu+ on the CV time scale. The Cu+ complexes were generated in situ by electrolysis and examined by NMR spectroscopy. DFT calculations gave further structural insights. These results demonstrate that the investigated sulfur-containing chelators are promising candidates for application in copper-based radiopharmaceuticals. In this connection, the high stability of both Cu2+ and Cu+ complexes can represent a key parameter for avoiding in vivo demetalation after bioinduced reduction to Cu+, often observed for other well-known chelators that can stabilize only Cu2+.

Early Evaluation of Copper Radioisotope Production at ISOLPHARM.

The ISOLPHARM (ISOL technique for radioPHARMaceuticals) project is dedicated to the development of high purity radiopharmaceuticals exploiting the radionuclides producible with the future Selective Production of Exotic Species (SPES) Isotope Separation On-Line (ISOL) facility at the Legnaro National Laboratories of the Italian National Institute for Nuclear Physics (INFN-LNL). At SPES, a proton beam (up to 70 MeV) extracted from a cyclotron will directly impinge a primary target, where the produced isotopes are released thanks to the high working temperatures (2000 °C), ionized, extracted and accelerated, and finally, after mass separation, only the desired nuclei are collected on a secondary target, free from isotopic contaminants that decrease their specific activity. A case study for such project is the evaluation of the feasibility of the ISOL production of 64Cu and 67Cu using a zirconium germanide target, currently under development. The producible activities of 64Cu and 67Cu were calculated by means of the Monte Carlo code FLUKA, whereas dedicated off-line tests with stable beams were performed at LNL to evaluate the capability to ionize and recover isotopically pure copper.

Altered plasma levels of decanoic acid in colorectal cancer as a new diagnostic biomarker.

Colorectal cancer (CRC) is one of the most common tumors in developed countries. The five-year survival rate decreases depending on how advanced the CRC is when first diagnosed. Screening has been proven to greatly reduce mortality from colorectal cancer, but an ideal screening tool is far from being established. Here, we aimed to discover and validate early CRC biomarkers by means of an untargeted/targeted metabolomic approach. A preliminary untargeted analysis of plasma lipids performed on a small patient cohort (30 plasma samples) revealed some alterations that occurred in the presence of this tumor. In particular, medium-chain fatty acids with between six and twelve carbon atoms (C6-C12) were found to be the lipid class that showed the most marked changes upon the development of CRC. In order to evaluate the utility of this lipid class as diagnostic CRC biomarkers, a further study based on a wider cohort of patients (117 plasma samples) was performed. Using a targeted approach, these fatty acids were quantified in plasma samples by means of fast gas chromatography coupled to a time-of-flight analyzer. Plasma samples from patients with CRCs at different tumor stages were analyzed and compared to those from healthy subjects, ulcerative colitis patients, high-grade dysplasia adenoma patients, and breast cancer patients in order to test the specificity and sensitivity of these possible biomarkers. Results revealed significant differences among the considered groups in terms of their C6, C8, C10, and C12 fatty acid plasma concentrations. In particular, receiver operating characteristic (ROC) curves obtained for the C10 fatty acid gave an area under the curve of 0.8195 along with a sensitivity of 87.8 % and a specificity of 80 %, strongly suggesting that it could be a valuable early diagnostic biomarker of CRC.

Navigating through the coordination preferences of heavy alkaline earth metals: Laying the foundations for 223Ra- and 131/135mBa-based targeted alpha therapy and theranostics of cancer.

The clinical success of [223Ra]RaCl2 (Xofigo®) for the palliative treatment of bone metastases in patients with prostate cancer has highlighted the therapeutic potential of α-particle emission. Expanding the applicability of radium-223 in Targeted Alpha Therapy of non-osseous tumors is followed up with significant interest, as it holds the potential to unveil novel treatment options in the comprehensive management of cancer. Moreover, the use of barium radionuclides, like barium-131 and -135m, is still unfamiliar in nuclear medicine applications, although they can be considered as radium-223 surrogates for imaging purposes. Enabling these applications requires the establishment of chelators able to form stable complexes with radium and barium radionuclides. Until now, only a limited number of ligands have been suggested and these molecules have been primarily inspired by existing structures known for their ability to complex large metal cations. However, a systematic inspection of chelators specifically tailored to Ra2+ and Ba2+ has yet to be conducted. This work delves into a comprehensive investigation of a series of small organic ligands, aiming to unveil the coordination preferences of both radium-223 and barium-131/135m. Electronic binding energies of both metal cations to each ligand were theoretically computed via Density Functional Theory calculations (COSMO-ZORA-PBE-D3/TZ2P), while thermodynamic stability constants were experimentally determined for Ba2+-ligand complexes by potentiometry, NMR and UV-Vis spectroscopies. The outcomes revealed malonate, 2-hydroxypyridine 1-oxide and picolinate as the most favorable building blocks to design multidentate chelators. These findings serve as foundation guidelines, propelling the development of cutting-edge radium-223- and barium-131/135m-based radiopharmaceuticals for Targeted Alpha Therapy and theranostics of cancer.

Different approaches to the study of chelating agents for iron and aluminium overload pathologies.

Our objective is to illustrate the activity of the groups operating in Italy involved in identification and study of new chelating agents, mainly intended for treatment of human pathology correlated with metal overload. The objective of "chelation therapy" is removal of toxic metal ions from the human body or attenuation of their toxicity by transforming them into less toxic compounds or by dislocating them from the site at which they exert a toxic action. Because most of this research activity is related to chelating agents for iron and aluminium, diseases related to these two metal ions are briefly treated. Iron overload is the most common metal toxicity disease worldwide. The toxicity of aluminium in dialysis patients was a serious problem for haemodialysis units in the seventies and eighties of the last century. In particular, this review focuses on research performed by the group at Cagliari and Ferrara, and by that at Padova. The former is studying, above all, bisphosphonate and kojic acid derivatives, and the latter is investigating 3,4-hydroxypyridinecarboxylic acids with differently substituted pyridinic rings.

The Curies' element: state of the art and perspectives on the use of radium in nuclear medicine.

BACKGROUND: The alpha-emitter radium-223 (223Ra) is presently used in nuclear medicine for the palliative treatment of bone metastases from castration-resistant prostate cancer. This application arises from its advantageous decay properties and its intrinsic ability to accumulate in regions of high bone turnover when injected as a simple chloride salt. The commercial availability of [223Ra]RaCl2 as a registered drug (Xofigo®) is a further additional asset. MAIN BODY: The prospect of extending the utility of 223Ra to targeted α-therapy of non-osseous cancers has garnered significant interest. Different methods, such as the use of bifunctional chelators and nanoparticles, have been explored to incorporate 223Ra in proper carriers designed to precisely target tumor sites. Nevertheless, the search for a suitable scaffold remains an ongoing challenge, impeding the diffusion of 223Ra-based radiopharmaceuticals. CONCLUSION: This review offers a comprehensive overview of the current role of radium radioisotopes in nuclear medicine, with a specific focus on 223Ra. It also critically examines the endeavors conducted so far to develop constructs capable of incorporating 223Ra into cancer-targeting drugs. Particular emphasis is given to the chemical aspects aimed at providing molecular scaffolds for the bifunctional chelator approach.

Chromatographic separation of silver-111 from neutron-irradiated palladium target: toward direct labeling of radiotracers.

BACKGROUND: Silver-111 is a promising ß--emitting radioisotope with ideal characteristics for targeted radionuclide therapy and associated single photon emission tomography imaging. Its decay properties closely resemble the clinically established lutetium-177, making it an attractive candidate for therapeutic applications. In addition, the clinical value of silver-111 is further enhanced by the existence of the positron-emitting counterpart silver-103, thus imparting a truly theranostic potential to this element. A so-fitting matching pair could potentially overcome the current limitations associated with the forced use of chemically different isotopes as imaging surrogates of lutetium-177, leading to more accurate and efficient diagnosis and treatment. However, the use of silver-111-based radiopharmaceuticals in vivo has faced obstacles due to the challenges related to its production and radiochemical separation from the target material. To address these issues, this study aims to implement a chromatographic separation methodology for the purification of reactor-produced silver-111. The ultimate goal is to achieve a ready-to-use formulation for the direct radiolabeling of tumour-seeking biomolecules. RESULTS: A two-step sequence chromatographic process was validated for cold Ag-Pd separation and then translated to the radioactive counterpart. Silver-111 was produced via the 110Pd(n,γ)111Pd nuclear reaction on a natural palladium target and the subsequent ß--decay of palladium-111. Silver-111 was chemically separated from the metallic target via the implemented chromatographic process by using commercially available LN and TK200 resins. The effectiveness of the separations was assessed by inductively coupled plasma optical emission spectroscopy and γ-spectrometry, respectively, and the Ag+ retrieval was afforded in pure water. Recovery of silver-111 was > 90% with a radionuclidic purity > 99% and a separation factor of around 4.21·10-4. CONCLUSIONS: The developed separation method was suitable to obtain silver-111 with high molar activity in a ready-to-use water-based formulation that can be directly employed for the labeling of radiotracers. By successfully establishing a robust and efficient production and purification method for silver-111, this research paves the way for its wider application in targeted radionuclide therapy and precision imaging.

Mass spectrometic study of speciation in aluminium-fluoroquinolone solutions.

Fluoroquinolones (FQLs) are synthetic antibacterial agents containing a 4-oxo-1,4-dihydroquinoline skeleton. When concomintantly administered with other drugs which may contain metal ions, particularly Al(3+) (antacids, phosphate binders, vaccines etc) they may form metal-drug complexes. Pharmacokinetic studies showed that aluminium-quinolone interactions lead to reduced bio- availability and altered activity of the drug with possible development of the toxic effects of aluminum ion. Reliable speciation in Al(3+) - quinolone systems at micromolar concentration level is needed to better understand pharmaco- and toxicokinetics of the FQLs in the presence of Al. In this work, the speciation in solutions containing Al(3+) and FQL family members (fleroxacin, moxifloxacin and ciprofloxacin) was studied by electrospray mass spectrometry (ESI-MS), ESI-MS/MS, and laser desorption ionization (LDI) MS. The dominating species identified in all the three Al(3+)-FQL solutions, at ca 30-50 µmol L(-1) total Al concentration and 2:1 to 1:3 metal-to-ligand ratio in the pH range 3.0- 6.0, were the ions related to the complexes AlL(2+), AlL(2)(+) and AlL(3)(0) (L = ligand in the monodeprotonated form). Mixed protonated and hydroxo complexes were also formed at lower and higher pH values respectively and, as expected, dimeric and polymeric species were not observed in ESI spectra. LDI measurements confirmed the existence of the mononuclear complexes found by ESI, and indicated the formation of polymeric species. The ion [2Al(3+) +5(-)](+) was identified with all three FQLs. This ionic species most probably arises from Al(2)L(2) by clustering with free ligand anions. Comparison of literature potentiometric data with mass spectral data indicated good agreement between speciation schemes. The obtained results suggest the presence of strong interaction between FQLs and Al(3+) which may be important in affecting absorption of these drugs in the gastrointestinal tract.

Bismuth chelation for targeted alpha therapy: Current state of the art.

Current interest in the α-emitting bismuth radionuclides, bismuth-212 (212Bi) and bismuth-213 (213Bi), stems from their great potential for targeted alpha therapy (TAT), an expanding and promising approach for the treatment of micrometastatic disease and the eradication of single malignant cells. To selectively deliver their emission to the cancer cells, these radiometals must be firmly coordinated by a bifunctional chelator (BFC) attached to a tumour-seeking vector. This review provides a comprehensive overview of the current state-of-the-art chelating agents for bismuth radioisotopes. Several aspects are reported, from their 'cold' chelation chemistry (thermodynamic, kinetic, and structural properties) and radiolabelling investigations to the preclinical and clinical studies performed with a variety of bioconjugates. The aim of this review is to provide both a guide for the rational design of novel optimal platforms for the chelation of these attractive α-emitters and emphasize the prospects of the most encouraging chelating agents proposed so far.

Towards in vivo applications of 111Ag perturbed angular correlation of γ-rays (PAC) spectroscopy.

111Ag-perturbed angular correlation of γ-rays (PAC) spectroscopy provides information on the nuclear quadrupole interactions, and thereby on the local structure and dynamics of the silver ion binding site. Brownian rotational motion, i.e. rotational diffusion, of 111Ag-labeled molecules will significantly affect the PAC spectra. Here we illustrate this effect, by simulating 111Ag PAC spectra for 111Ag-labeled molecules with molecular masses spanning from 102 to 106 g/mol, reflecting a span from fast (small molecules) to slow (large molecules) rotational diffusion on the PAC time scale. The simulated spectra are compared to 111Ag-PAC data obtained from a pilot study involving 111Ag(I) bound to a designed chelator exhibiting fast reorientation in solution, as well as to 111Ag-labeled species formed by 111Ag(I) in human serum, exhibiting slow (or no) reorientation on the PAC time scale. The simulated and experimental data illustrate typical PAC signals that are likely to be observed in vivo, when following the fate of 111Ag-labeled compounds. Potential in vivo applications are stability studies of 111Ag-radiopharmaceuticals, dissociation studies of 111Ag from the labeled molecule followed by binding to another (bio)molecule, or binding of 111Ag-labeled probes to larger carriers such as proteins.

Emerging investigator series: aqueous-phase processing of atmospheric aerosol influences dissolution kinetics of metal ions in an urban background site in the Po Valley.

Metals are an important atmospheric aerosol component; their impacts on health and the environment depend also on their solubility, dissolution kinetics and chemical form in which they are present in the aerosol (e.g., oxidation state, inorganic salt or oxide/hydroxide, organic complex). In this study, we investigated the impact of fog processing on the solubility and dissolution of metals in PM2.5 samples collected in an urban background site in Padova (Italy). For each sample, we determined the solubility and dissolution kinetics of 17 elements in a solution simulating fog water in the winter season in the Po Valley (pH 4.7, T 5 °C, and water content ∼0.5 g m-3). We also determined water-soluble inorganic and organic compounds having ligand properties. We used the model E-AIM IV to calculate the aerosol liquid water (ALW) content and pH, and we used the model Visual MinteQ to determine the speciation picture of the most important elements under conditions of both deliquescent aerosol (ALW and pH calculated using E-AIM IV, ambient temperature) and simulated fog. We found that the dissolution of Al, Cu, and Fe metal ions, predicted to be largely coordinated with organic compounds under fog conditions, was either immediate or considerably faster in samples collected on days with observed fog events compared with those collected on days having drier conditions. For readily soluble elements, such as As, Cd, Cr, Sr, and Zn, such an effect was not observed. Our study highlights the importance of coordination chemistry in atmospheric aerosol and fog in determining the bioavailability of particle-bound metals.

Crystal structures of zinc(II) complexes with ß-hydroxypyridinecarboxylate ligands: examples of structure-directing effects used in inorganic crystal engineering.

The coordination properties of four hydroxypyridinecarboxylates, designed for the treatment of iron-overloading conditions as bidentate O,O'-donor ligands, have been studied with ZnII in the solid state. The coordination compounds [Zn(A1)2(H2O)2] (1), [Zn(A2)2(H2O)] (2), [Zn(A3)2(H2O)]·2H2O (3) and [Zn2(B1)4(H2O)2]·4H2O (4), where the ligands are 1-methyl-4-oxidopyridinium-3-carboxylate (A1, C7H6NO3), 1,6-dimethyl-4-oxidopyridinium-3-carboxylate (A2, C8H8NO3), 1,5-dimethyl-4-oxido-pyridinium-3-carboxylate (A3, C8H8NO3) and 1-methyl-3-oxidopyridinium-4-carboxylate (B1, C7H6NO3), have been synthesized and analysed by single-crystal X-ray diffraction. The ligands were chosen to probe (i) the electronic effects of inverting the positions of the O-atom donor groups (i.e. A1 versus B1) and (ii) the electronic and steric effects of the addition of a second methyl group in different positions on the pyridine ring. Two axially coordinated water molecules resulting in a six-coordinated symmetrical octahedron complement the bis-ligand complex of A1. Ligands A2 and A3 form five-coordinated trigonal bipyramidal complexes with one additional water molecule in the coordination sphere, which is a rarely reported geometry for ZnII complexes. Ligand B1 shows a dimeric structure, where the two Zn2+ dications have slightly distorted octahedral geometry and the pyridinolate O atom of the neighbouring complex bridges them. The coordination spheres of the Zn2+ dications and the supramolecular structures are discussed in detail. The packing arrangements of 1-3 are similar, having alternating hydrophilic and hydrophobic layers, however the similarity is broken in 4. The obtained coordination geometries are compared with their previously determined CuII analogues. The study of the individual complexes is complemented with a comprehensive analysis of ZnII complexes with oxygen donor ligands with data from the Cambridge Structural Database.

Use of a simple empirical model for the accurate conversion of the seawater pH value measured with NIST calibration into seawater pH scales.

The seawater pH measurement is usually quite complicated because that matrix is characterized by a high ionic strength leading to calibration errors if NIST standards are used. For this matrix, different pH scales like the "total hydrogen ion concentration scale" (TOT) and the "seawater scale" (SWS), are defined, and suitable synthetic seawater solutions must be prepared according to standard procedures to calibrate the glass electrode. This work provides a new approach to make seawater pH measurements by using the glass electrode calibrated with the NIST standards (pHNIST) converting the pHNIST into the right TOT or SWS scales by using empirical equations derived from theoretical thermodynamic data: pHTOT=pHNIST+0.10383+4.33⋅10-5TS+3.633⋅10-5T2-4.921⋅10-5S2, and pHSWS=pHNIST+0.097733+4.1059⋅10-5TS+3.5437⋅10-5T2-4.941⋅10-5S2, for the TOT and SWS scales, respectively. These equations are functions of two simple experimental parameters, namely, T = temperature (°C) and S = salinity (PSU, (g/L), Practical Salinity Units). These equations were experimentally validated and the uncertainty of pHTOT and pHSWS was demonstrated to have no statistical difference with the corresponding values obtained following the standard operative procedure (SOP) using commercially unavailable seawater-like buffers. The proposed method has therefore the same performances and it is largely preferable as it avoids long and tedious procedures of the synthetic seawater preparations.

New insights in the slow ligand exchange reaction between Cr(III)-EDTA and Fe(III), and direct analysis of free and complexed EDTA in tannery wastewaters by liquid chromatography - Tandem mass spectrometry.

EDTA and soluble Cr(III) are usually both present in wastewaters coming from treatment plants handling tannery effluents. A well-established method to determine EDTA is based on the conversion of free and complexed EDTA into its Fe(III) complex. This procedure gives inconsistent data when Cr(III)-EDTA is present. This fact was here demonstrated by studying the kinetics of the exchange reaction between Fe(III) and Cr(III)-EDTA at 90 °C and various pH values, from acidic to neutral. The reaction is very slow (several weeks); the slow kinetics of conversion of Cr(III)-EDTA to Fe(III)-EDTA is even more accentuated at room temperature and the low concentrations of reactants in wastewaters. The presence of EDTA complexes of Fe(III) and Cr(III) was demonstrated in industrial effluents and wastewaters by developing a selective method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS), which was able to detect free and complexed EDTA at concentration levels <1 µM. A systematic underestimation of the EDTA expressed as Fe(III) complex was demonstrated in samples containing Cr(III)-EDTA. Cr(III)-EDTA was identified for the first time as a component of wastewater samples at a concentration level of about 2 µM and turned out to be an inert species that significantly contributes to the final soluble Cr amount. This study gives new insights into the inertness of Cr(III) toward metal exchange equilibria of EDTA complexes, resolves a bias in the analysis of total EDTA in samples containing Cr(III)-EDTA, allowing the direct determination of free and complexed EDTA by LC-MS.