Htrica: Versatile Macrocyclic Chelator for [Ac]Ac and [Tb]Tb Theranostics.

Htrica is a nonadentate chelating ligand intended for coordinating large radiometal ions, such as those used in nuclear medicine. This chelator, featuring a triaza-18-crown-6 macrocycle with three pendant carboxylic acid functional groups, was synthesized and characterized. Complementary nuclear magnetic resonance (NMR) spectroscopy and high-resolution electrospray-ionization mass spectroscopy (HR-ESI-MS) studies were used to explore the coordination of Htrica with metal ions such as La, Y (as a model for Tb, and Lu at the bulk scale.

Rearmed Bifunctional Chelating Ligand for Ac/Tb Precision-Guided Theranostic Radiopharmaceuticals─HnoneunpaX.

Superior bifunctional chelating ligands, which can sequester both α-emitting radionuclides (Ac, Bi) and their diagnostic companions (Tb, In), remain a formidable challenge to translating targeted alpha therapy, with complementary diagnostic imaging, to the clinic. HnoneupaX, a chelating ligand with an unusual diametrically opposed arrangement of pendant donor groups, has been developed to this end. HnoneunpaX preferentially complexes Ln and An ions, forming thermodynamically stable (pLa = 17.

Smart thrombosis inhibitors without bleeding side effects via charge tunable ligand design.

Current treatments to prevent thrombosis, namely anticoagulants and platelets antagonists, remain complicated by the persistent risk of bleeding. Improved therapeutic strategies that diminish this risk would have a huge clinical impact. Antithrombotic agents that neutralize and inhibit polyphosphate (polyP) can be a powerful approach towards such a goal.

Toward Ga and Cu Positron Emission Tomography Probes: Is Hdedpa-,'-pram the Missing Link for dedpa Conjugation?

Hdedpa-,'-pram (HL), a new chelator derived from the hexadentate ligand 1,2-bis[[(6-carboxypyridin-2-yl)methyl]amino]ethane (Hdedpa), which incorporates 3-propylamine chains anchored to the secondary amines of the ethylenediamine core of the latter, has emerged as a very promising scaffold for preparing Ga- and Cu-based positron emission tomography probes. This new platform is cost-effective and easy to prepare, and the two pendant primary amines make it versatile for the preparation of bifunctional chelators by conjugation and/or click chemistry. Reported herein, we have also included the related Hdedpa-,'-prpta (HL) platform as a simple structural model for its conjugated systems.

Hpicoopa─Robust Chelate for Ac/In Theranostics.

The nuclear decay characteristics of Ac ( = 5-8 MeV, linear energy transfer (LET) = ∼100 keV/μm, = 9.92 days) are well recognized as advantageous for the treatment of primary and metastatic tumors; however, suitable chelation systems are required, which can accommodate this radiometal. Since Ac does not possess any suitable low-energy, high abundance γ-ray emissions for nuclear imaging, there is a clear need for the development of other companion radionuclides with similar coordination characteristics and comparable half-lives, which can be applied in diagnostics.

Hampa─Versatile Chelator for [Pb]Pb, [Bi]Bi, and [Ac]Ac.

A new decadentate chelator, Hampa, was designed to be a potential radiopharmaceutical chelator component. The chelator involves both amide and picolinate functional groups on a large non-macrocyclic, ether-bridged backbone. With its large scaffold, Hampa was paired with [Pb]Pb, [Bi]Bi, and La/[Ac]Ac ions.

Metal ion size profoundly affects Hglyox chelate chemistry.

The bisoxine hexadentate chelating ligand, Hglyox was investigated for its affinity for Mn, Cu and Lu ions; all three metal ions are relevant with applications in nuclear medicine and medicinal inorganic chemistry. The aqueous coordination chemistry and thermodynamic stability of all three metal complexes were thoroughly investigated by detailed DFT structure calculations and stability constant determination, by employing UV in-batch spectrophotometric titrations, giving pM values (pM = -log[M ] when [M ] = 1 μM, [L] = 10 μM at pH 7.4 and 25 °C) - pCu (25.

Bis(amido)bis(oxinate)diamine Ligands for theranostic radiometals.

With the interest in radiometal-containing diagnostic and therapeutic pharmaceuticals increasing rapidly, appropriate ligands to coordinate completely and stably said radiometals is essential. Reported here are two novel, bis(amido)bis(oxinate)diamine ligands, Hamidohox (2,2'-(ethane-1,2-diylbis(((8-hydroxyquinolin-2-yl)methyl)azanediyl))diacetamide) and HamidoC3hox (2,2'-(propane-1,3-diylbis(((8-hydroxyquinolin-2-yl)methyl)azanediyl))diacetamide), that combine two 8-hydroxyquinoline and amide donor groups and differ by one carbon in their 1,2-ethylenediamine vs. 1,3-diaminopropane backbones, respectively.

[Zr][Zr(pypa)]: Thermodynamically Stable and Kinetically Inert Binary Nonadentate Complex for Radiopharmaceutical Applications.

Hpypa is a nonadentate nonmacrocyclic chelator, which previously demonstrated high affinity for scandium-44, lutetium-177, and indium-111. Herein, we report the highly stable binary [Zr(pypa)] complex; the nonradioactive complex was synthesized and characterized in detail using high-resolution electrospray-ionization mass spectroscopy (HR-ESI-MS) and various nuclear magnetic resonance spectroscopies (NMR), which revealed symmetry of the complex. The geometry of [Zr(pypa)] was further detailed via X-ray crystallography and compared with the structure of [Fe(Hpypa)].

HHBEDpa: Octadentate Chelate after A. E. Martell.

HHBEDpa, a new octadentate chelator inspired by the 1960s ligand HBED of Arthur E. Martell, has been investigated for a selection of trivalent metal ions useful in diagnostic and therapeutic applications (Sc, Fe, Ga, In, and Lu). Complex formation equilibria were thoroughly investigated using combined potentiometric and UV-vis spectrophotometric titrations which revealed effective chelation and high metal-sequestering capacity, in particular for Fe, log = 36.

Getting a lead on Pb-amide chelators for Pb radiopharmaceuticals.

Amide-based chelators DTPAm, EGTAm and ampam were synthesized to investigate which chelator most ideally coordinates [Pb]Pb ions for potential radiopharmaceutical applications. H NMR spectroscopy was used to study each metal-ligand complex in the solution state. The H NMR spectrum of [Pb(DTPAm)] revealed minimal isomerization and fluxional behaviour compared to [Pb(EGTAm)] and [Pb(ampam)], both of which showed fewer spectral changes indicative of less static behaviour.

Hpyhox - Octadentate Bis(pyridyloxine).

A new versatile chelating ligand for intermediate size and softness radiometals [Cu]Cu and [In]In, Hpyhox, was synthesized by introducing pyridine as a new donor moiety to complement 8-hydroxyquinoline on an ethylenediamine backbone. The combination of pyridine and oxine as donor sets was explored through structural analysis, and crystals of the three metal complexes with Cu, La, and In demonstrate how the ligand adapts to accommodate metal ions of different sizes and charge. Exhaustive in-batch UV solution studies characterized the protonation constants of the free ligand as well as the formation constants of the metal complexes with Cu, In, and La.

Phosphonate Chelators for Medicinal Metal Ions.

A family of phosphonate-bearing chelators was synthesized to study their potential in metal-based (radio)pharmaceuticals. Three ligands (Hphospa, Hdipedpa, Heppy; structures illustrated in manuscript) were fully characterized, including X-ray crystallographic structures of Hphospa and Hdipedpa. NMR spectroscopy techniques were used to confirm the complexation of each ligand with selected trivalent metal ions.

High denticity oxinate-linear-backbone chelating ligand for diagnostic radiometal ions [In]In and [Zr]Zr.

Advances in nuclear medicine depend on chelating ligands that form highly stable and kinetically inert complexes with relevant radiometal ions for use in diagnosis or therapy. A new potentially decadentate ligand, Hdecaox, was synthesised to incorporate two 8-hydroxyquinoline moieties on either end of a diethylenetriamine backbone decorated with three carboxylic acids, one at each N atom of the backbone. Metal complexation was assessed using nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectrometry (HR-MS) with In, Zr and La.

Rapid Thermodynamically Stable Complex Formation of [In]In, [Y]Y, and [Lu]Lu with Hdappa.

A phosphinate-bearing picolinic acid-based chelating ligand (Hdappa) was synthesized and characterized to assess its potential as a bifunctional chelator (BFC) for inorganic radiopharmaceuticals. Nuclear magnetic resonance (NMR) spectroscopy was employed to investigate the chelator coordination chemistry with a variety of nonradioactive trivalent metal ions (In, Lu, Y, Sc, La, Bi). Density functional theory (DFT) calculations explored the coordination environments of aforementioned metal complexes.

Coordination chemistry of [Y(pypa)] and comparison immuno-PET imaging of [Sc]Sc- and [Y]Y-pypa-phenyl-TRC105.

Both scandium-44 and yttrium-86 are popular PET isotopes with appropriate half-lives for immuno-positron emission tomography (immuno-PET) imaging. Herein, a new bifunctional Hpypa ligand, Hpypa-phenyl-NCS, is synthesized, conjugated to a monoclonal antibody, TRC105, and labeled with both radionuclides to investigate the long-term in vivo stability of each complex. While the Sc-labeled radiotracer exhibited promising pharmacokinetics and stability in 4T1-xenograft mice (n = 3) even upon prolonged interactions with blood serum proteins, the progressive bone uptake of the Y-counterpart indicated in vivo demetallation, obviating Hpypa as a suitable chelator for Y ion in vivo.

Ac-Hpy4pa for Targeted Alpha Therapy.

Herein, we present the syntheses and characterization of a new undecadendate chelator, Hpy4pa, and its bifunctional analog Hpy4pa-phenyl-NCS, conjugated to the monoclonal antibody, Trastuzumab, which targets the HER2+ cancer. Hpy4pa possesses excellent affinity for Ac (α, = 9.92 d) for targeted alpha therapy (TAT), where quantitative radiolabeling yield was achieved at ambient temperature, pH = 7, in 30 min at 10 M chelator concentration, leading to a complex highly stable in mouse serum for at least 9 d.

Hhox: Rigid Cyclohexane-Reinforced Nonmacrocyclic Chelating Ligand for [Ga]Ga.

A rigid chiral acyclic chelator Hhox was synthesized and evaluated for Ga-based radiopharmaceutical applications; it was compared to the previously reported hexadentate Hhox to determine the effect of a backbone reinforced from adding a chiral 1S,2S-trans-cyclohexane on metal complex stability, kinetic inertness, and pharmacokinetics. NMR spectroscopy and theoretical calculation revealed that [Ga(hox)] showed a very similar coordination geometry to that of [Ga(hox)], and only one isomer in solution was observed by NMR spectroscopy. Solution studies showed that the modification results in a significant improvement in the exceptionally high thermodynamic stability of [Ga(hox)] with a 1.

[Sc(pypa)]: Thermodynamic Stability, Radiolabeling, and Biodistribution of a Prostate-Specific-Membrane-Antigen-Targeting Conjugate.

Sc is an attractive positron-emitting radionuclide for PET imaging; herein, a new complex of the Sc ion with nonmacrocyclic chelator Hpypa was synthesized and characterized with high-resolution electrospray-ionization mass spectrometry (HR-ESI-MS), as well as different nuclear magnetic resonance (NMR) spectroscopic techniques (H, C, H-C HSQC, H-C HMBC, COSY, and NOESY). In aqueous solution (pH = 7), [Sc(pypa)] presented two isomeric forms, the structures of which were predicted using density functional theory (DFT) calculation with a small energy difference of 22.4 kJ/mol, explaining their coexistence.

Evaluation of the Tetrakis(3-Hydroxy-4-Pyridinone) Ligand THPN with Zirconium(IV): Thermodynamic Solution Studies, Bifunctionalization, and in Vivo Assessment of Macromolecular Zr-THPN-Conjugates.

Zirconium-89 (Zr) is a suitable radionuclide for positron-emission tomography (PET) of long-circulating targeting vectors such as monoclonal antibodies (mAbs). Due to stability concerns for the most widely used Zr-chelating agent desferrioxamine B (DFO) in preclinical studies, alternative Zr-chelators are currently being developed. We recently reported on the first tetrakis(3-hydroxy-4-pyridinone) (3,4-HOPO) ligand THPN, which was identified as a promising Zr-chelator.

Functionally Versatile and Highly Stable Chelator for In and Lu: Proof-of-Principle Prostate-Specific Membrane Antigen Targeting.

Here, we present the synthesis and characterization of a new potentially nonadentate chelator Hpypa and its bifunctional analogue Bupypa-C7-NHS conjugated to prostate-specific membrane antigen (PSMA)-targeting peptidomimetic (Glu-urea-Lys). Hpypa is very functionally versatile and biologically stable. Compared to the conventional chelators (e.

A new tripodal kojic acid derivative for iron sequestration: Synthesis, protonation, complex formation studies with Fe, Al, Cu and Zn, and in vivo bioassays.

This work presents the simple and low cost synthesis of a new tripodal ligand, in which three units of kojic acid are coupled to a tris(2-aminoethyl)amine (tren) backbone molecule. The protonation equilibria, together with the complex formation equilibria of this ligand with Fe, Al, Cu and Zn ions were studied. The complementary use of potentiometric, spectrophotometric and NMR techniques, and of Density Functional Theory (DFT) calculations, has allowed a thorough characterization of the different species involved in equilibrium.

Hoctox: Versatile Bimodal Octadentate Acyclic Chelating Ligand for Medicinal Inorganic Chemistry.

Hoctox, a versatile new octadentate acyclic chelating ligand, has been investigated as an alternative to the acyclic DTPA and the macrocyclic DOTA for trivalent metal ions useful in diagnostic medical imaging or therapeutic applications (Y, In, La, Gd, Lu). The synthesis of Hoctox is straightforward in less steps and thus more economical than those of most previously reported chelators. Complex formation equilibria in the presence of Y, In, La, Gd, and Lu revealed fast chelation and high metal-sequestering capacity.

Equilibrium studies of new bis-hydroxypyrone derivatives with Fe, Al, Cu and Zn.

This paper presents an easy and low cost synthesis of chelating agents for potential medical and environmental applications, and the evaluation of the stability of their complexes with Fe, Al, Cu and Zn. In the last years, we synthesized and characterized effective iron chelators based on two kojic acid units joined by different linkers in position 6. In this study, we preserved kojic acid (a cheap and non-toxic molecule) as the basic unit but joined the two kojic acid units through ethylene diamine, propylene diamine and butylene diamine by reacting them with the OH groups in position 2.

Hhox: Dual-Channel Oxine-Derived Acyclic Chelating Ligand for Ga Radiopharmaceuticals.

An acyclic hexadentate oxine-derived chelating ligand, Hhox, was investigated as an alternative to current chelators for Ga. The straightforward preparation of Hhox, involving only one or two steps, obviates the synthetic challenges associated with many reported Ga chelators; it forms a Ga complex of great stability (log K = 34.4) with a remarkably high gallium scavenging ability (pGa = -log[Ga] = 28.