Bridging pyrimidine hemicurcumin and Cisplatin: Synthesis, coordination chemistry, and in vitro activity assessment of a novel Pt(II) complex.

In the upcoming decades, the incidence and mortality rates of cancer are expected to rise globally, with colorectal and prostate cancers among the most prevalent types. Despite advancements in molecular targeted therapy, platinum-based chemotherapies remain the cornerstone of treatment, especially for colorectal and prostate cancer, with oxaliplatin and cisplatin being extremely effective due to their DNA-targeting capabilities. In our pursuit of new platinum-based chemotherapeutics that are potentially less toxic and more effective, we have explored the combination of the Pt-binding groups of the diaminocyclohexane ring used in oxaliplatin, with the stable amino-pyrimidine hemicurcumin moiety.

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

The interest in mercury radioisotopes, Hg ( = 23.8 h) and Hg ( = 64.14 h), has recently been reignited by the dual diagnostic and therapeutic nature of their nuclear decays.

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

The clinical success of [Ra]RaCl (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.

Exploration of commercial cyclen-based chelators for mercury-197 m/g incorporation into theranostic radiopharmaceuticals.

A comprehensive investigation of the Hg coordination chemistry and Hg radiolabeling capabilities of cyclen-based commercial chelators, namely, DOTA and DOTAM (aka TCMC), along with their bifunctional counterparts, -SCN-Bn-DOTA and -SCN-Bn-TCMC, was conducted to assess the suitability of these frameworks as bifunctional chelators for the Hg theranostic pair. Radiolabeling studies revealed that TCMC and DOTA exhibited low radiochemical yields (0%-6%), even when subjected to harsh conditions (80°C) and high ligand concentrations (10 M). In contrast, -SCN-Bn-TCMC and -SCN-Bn-DOTA demonstrated significantly higher Hg radiochemical yields (100% ± 0.

Evaluation of a novel hexadentate 1,2-hydroxypyridinone-based acyclic chelate, HOPO-O-C4, for Sc/Sc, Ga, and Ti radiopharmaceuticals.

Introduction: Chelators play a crucial role in the development of metal-based radiopharmaceuticals, and with the continued interest in Ga and increasing availability of new radiometals such as Sc/Sc and Ti, there is a growing demand for tailored chelators that can form stable complexes with these metals. This work reports the synthesis and characterization of a hexadentate tris-1,2-hydroxypyridonone chelator HOPO-O-C4 and its in vitro and in vivo evaluation with the above mentioned radiometals.

Methods: To investigate the affinity of HOPO-O-C4, macroscopic studies were performed with Sc, and Ga followed by DFT structural optimization of the Sc, Ga and Ti complexes.

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

A series of macrocyclic ligands were considered for the chelation of Pb: 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 Pb 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 Pb and that the most suitable macrocyclic scaffold for Pb is 1,4,7,10-tetrazacyclododecane.

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

Background: Silver-111 is a promising β-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.

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

Background: The alpha-emitter radium-223 (Ra) 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 [Ra]RaCl as a registered drug (Xofigo) is a further additional asset.

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 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.

Development of Stable Amino-Pyrimidine-Curcumin Analogs: Synthesis, Equilibria in Solution, and Potential Anti-Proliferative Activity.

With the clear need for better cancer treatment, naturally occurring molecules represent a powerful inspiration. Recently, curcumin has attracted attention for its pleiotropic anticancer activity in vitro, especially against colorectal and prostate cancer cells. Unfortunately, these encouraging results were disappointing in vivo due to curcumin's low stability and poor bioavailability.

Lights and Shadows on the Sourcing of Silver Radioisotopes for Targeted Imaging and Therapy of Cancer: Production Routes and Separation Methods.

The interest in silver radioisotopes of medical appeal (silver-103, silver-104m,g and silver-111) has been recently awakened by the versatile nature of their nuclear decays, which combine emissions potentially suitable for non-invasive imaging with emissions suited for cancer treatment. However, to trigger their in vivo application, the production of silver radioisotopes in adequate amounts, and with high radionuclidic purity and molar activity, is a key prerequisite. This review examines the different production routes of silver-111, silver-103 and silver-104m,g providing a comprehensive critical overview of the separation and purification strategies developed so far.

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

The biologically triggered reduction of Cu to Cu has been postulated as a possible decomplexation pathway in Cu-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 Cu complexes, a marked [Cu]Cu release was detected in human serum, likely as a result of the partially saturated coordination sphere around the copper center.

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 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 Hg into a radiopharmaceutical.

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

Ag-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.

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 Cu-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 Cu and Cu.

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

Current interest in the α-emitting bismuth radionuclides, bismuth-212 (Bi) and bismuth-213 (Bi), 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.

Revisiting Lead(II)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic Acid Coordination Chemistry in Aqueous Solutions: Evidence of an Underestimated Thermodynamic Stability.

The complexes formed between Pb and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) were reinvestigated in aqueous solutions using a combination of pH potentiometry, UV-vis spectroscopy, and NMR spectroscopy. The thermodynamic data were supported by kinetics assays. Differently protonated complexes, .

Efficient Production of High Specific Activity Thulium-167 at Paul Scherrer Institute and CERN-MEDICIS.

Thulium-167 is a promising radionuclide for nuclear medicine applications with potential use for both diagnosis and therapy ("theragnostics") in disseminated tumor cells and small metastases, due to suitable gamma-line as well as conversion/Auger electron energies. However, adequate delivery methods are yet to be developed and accompanying radiobiological effects to be investigated, demanding the availability of Tm in appropriate activities and quality. We report herein on the production of radionuclidically pure Tm from proton-irradiated natural erbium oxide targets at a cyclotron and subsequent ion beam mass separation at the CERN-MEDICIS facility, with a particular focus on the process efficiency.

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

The Cu 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-Cu competition experiments were performed to evaluate the stoichiometry and stability constants of the Cu 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.

Preliminary Study of a 1,5-Benzodiazepine-Derivative Labelled with Indium-111 for CCK-2 Receptor Targeting.

The cholecystokinin-2 receptor (CCK-2R) is overexpressed in several human cancers but displays limited expression in normal tissues. For this reason, it is a suitable target for developing specific radiotracers. In this study, a nastorazepide-based ligand functionalized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator (IP-001) was synthesized and labelled with indium-111.

Preliminary evaluation of the production of non-carrier added Ag as core of a therapeutic radiopharmaceutical in the framework of ISOLPHARM_Ag experiment.

Research in the field of radiopharmaceuticals is increasingly promoted by the widespread and growing interest in applying nuclear medicine procedures in both disease diagnosis and treatment. The production of radionuclides of medical interest is however a challenging issue. Along with the conventional techniques other innovative approaches are being investigated and, among those, the ISOLPHARM project is being developed at INFN-LNL (Istituto Nazionale di Fisica Nucleare - Laboratori Nazionali di Legnaro).

Highly Stable Silver(I) Complexes with Cyclen-Based Ligands Bearing Sulfide Arms: A Step Toward Silver-111 Labeled Radiopharmaceuticals.

With a half-life of 7.45 days, silver-111 (β 1.04 MeV, 245.

Chemical purification of Ag from isobaric impurity Cd by solid phase extraction chromatography: a proof of concept study.

Silver-111 (Ag, t = 7.47 d) is a β emitter suitable for targeted cancer therapy due to favourable decay properties. The production of no-carrier added Ag via Isotope Separation On-Line (ISOL) technique is being investigated at the Legnaro National Laboratories of the Italian Institute of Nuclear Physics (ISOLPHARM project).

Metal Chelation Therapy and Parkinson's Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs.

The present review reports a list of approximately 800 compounds which have been used, tested or proposed for Parkinson's disease (PD) therapy in the year range 2014-2019 (April): name(s), chemical structure and references are given. Among these compounds, approximately 250 have possible or established metal-chelating properties towards Cu(II), Cu(I), Fe(III), Fe(II), Mn(II), and Zn(II), which are considered to be involved in metal dyshomeostasis during PD. Speciation information regarding the complexes formed by these ions and the 250 compounds has been collected or, if not experimentally available, has been estimated from similar molecules.