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] = 28.3, ([Ga] = 1 μM; [L ] = 10 μM; pH 7.4, and 25 °C)). Moreover, Hhox coordinates Ga quantitatively in 5 min at room temperature in ligand concentrations as low as 1 × 10 M, achieving an unprecedented high molar activity of 11 ± 1 mCi/nmol (407 ± 3.7 MBq/nmol) without purification, suggesting prospective kit-based convenience. [Ga(hox)] showed no decomposition in a plasma challenge. Good in vivo stability and fast renal and hepatic clearance of the [Ga(hox)] complex were demonstrated using dynamic positron emission tomography/computed tomography imaging. The intrinsic fluorescence of [Ga(hox)] allowed for direct fluorescence imaging of cellular uptake and distribution, demonstrating the dual-channel detectability and intracellular stability of the metal complex.

Herein, we present the syntheses and characterization of a new undecadendate chelator, H4py4pa, and its bifunctional analog H4py4pa-phenyl-NCS, conjugated to the monoclonal antibody, Trastuzumab, which targets the HER2+ cancer. H4py4pa possesses excellent affinity for 225Ac (α, t 1/2 = 9.92 d) for targeted alpha therapy (TAT), where quantitative radiolabeling yield was achieved at ambient temperature, pH = 7, in 30 min at 10–6 M chelator concentration, leading to a complex highly stable in mouse serum for at least 9 d. To investigate the chelation of H4py4pa with large metal ions, lanthanum (La3+), which is the largest nonradioactive metal of the lanthanide series, was adopted as a surrogate for 225Ac to enable a series of nonradioactive chemical studies. In line with the 1H NMR spectrum, the DFT (density functional theory)-calculated structure of the [La­(py4pa)]− anion possessed a high degree of symmetry, and the La3+ ion was secured by two distinct pairs of picolinate arms. Furthermore, the [La­(py4pa)]− complex also demonstrated a superb thermodynamic stability (log K [La(py4pa)] – ∼ 20.33, pLa = 21.0) compared to those of DOTA (log K [La(DOTA)] – ∼ 24.25, pLa = 19.2) or H2macropa (log K [La(macropa)] – = 14.99, pLa ∼ 8.5). Moreover, the functional versatility offered by the bifunctional py4pa precursor permits facile incorporation of various linkers for bioconjugation through direct nucleophilic substitution. In this work, a short phenyl-NCS linker was incorporated to tether H4py4pa to Trastuzumab. Radiolabeling studies, in vitro serum stability, and animal studies were performed in parallel with the DOTA-benzyl-Trastuzumab. Both displayed excellent in vivo stability and tumor specificity.

H 4 octox, 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 3+ , In 3+ , La 3+ , Gd 3+ , Lu 3+ ). The synthesis of H 4 octox is straightforward in less steps and thus more economical than those of most previously reported chelators. Complex formation equilibria in the presence of Y 3+ , In 3+ , La 3+ , Gd 3+ , and Lu 3+ revealed fast chelation and high metal-sequestering capacity. Quantitative labeling with 111 In 3+ was achieved within 15 min at room temperature at ligand concentrations as low as 10 −7 M, exactly the properties required for the development of kit-based radiopharmaceuticals. In vitro serum stability studies and in vivo SPECT imaging confirmed excellent complex stability of [ 111 In-(octox)] − . Moreover, it is more lipophilic than most of the multidentate carboxylate-or picolinate-based chelators; it therefore shows more liver clearance and provides a complementary choice in the design of metal-based pharmaceuticals and in the tuning of their pharmacokinetic properties. Finally, H 4 octox showed a large fluorescence enhancement upon complexation with different metals, in particular, with Y 3+ and Lu 3+ , which could be useful for non-radioactive fluorescent stability and cell studies as well as bimodal imaging. Excellent in vitro stability of [Y(octox)] − against transferrin and Fe 3+ was confirmed employing this fluorescence.

Hoctapa is an extremely versatile acyclic chelator for a wide variety of medicinally relevant metal ions, forming complexes of both high thermodynamic and kinetic stability. This work reports a significantly simplified 3 step high yield straightforward synthesis of Hoctapa directly from EDDA. Crystals of the octa-protonated form of the ligand [Hoctapa] as its tetrachloride salt, and of the mixed lanthanum-sodium salt of [La(octapa)] were isolated and characterized by X-ray diffraction. All eight protonation constants for the ligand were determined through combined potentiometric-spectrophotometric titrations and in batch experiments using UV spectrophotometry and H NMR spectroscopy. Synthesis, characterisation and solution equilibria studies are presented for complexes [Ln(octapa)] (Ln = lanthanide element) with Sm(iii), Dy(iii), and Yb(iii) (each of which have radiopharmaceutical applications). Complex formation equilibria studies provided evidence of Ln(Hoctapa), [Ln(octapa)] and [Ln(octapa)(OH)] species in solution, and their stability constants were evaluated by pH-potentiometric competition titrations using [ttha] as a competing ligand, and by UV-vis spectrophotometric measurements. The high stability constants of the [Ln(octapa)] complexes with Sm(iii), Dy(iii), and Yb(iii) (log K = 20.10(2), log K = 20.14(3) and log K = 19.90(1)) are similar to the published values for other lanthanides and consequently these initial investigations confirm Hoctapa as a valuable ligand for Sm(iii), Dy(iii), Yb(iii) and other Ln for application in diagnostic and therapeutic nuclear medicine.

[44/47Sc]­Sc3+, [68Ga]­Ga3+, and [111In]­In3+ are the three most attractive trivalent smaller radiometalnuclides, offering a wide range of distinct properties (emission energies and types) in the toolbox of nuclear medicine. In this study, all three of the metal ions are successfully chelated using a new oxine-based hexadentate ligand, H3glyox, which forms thermodynamically stable neutral complexes with exceptionally high pM values [pIn (34) > pSc (26) > pGa (24.9)]. X-ray diffraction single crystal structures with stable isotopes revealed that the ligand is highly preorganized and has a perfect fit to size cavity to form [Sc­(glyox)­(H2O)] and [In­(glyox)­(H2O)] complexes. Quantitative radiolabeling with gallium-68 (RCY > 95%, [L] = 10–5 M) and indium-111 (RCY > 99%, [L] = 10–8 M) was achieved under ambient conditions (RT, pH 7, and 15 min) with very high apparent molar activities of 750 MBq/μmol and 650 MBq/nmol, respectively. Preliminary quantitative radiolabeling of [44Sc]­ScCl3 (RCY > 99%, [L] = 10–6 M) was fast at room temperature (pH 7 and 10 min). In vitro experiments revealed exceptional stability of both [68Ga]­Ga­(glyox) and [111In]­In­(glyox) complexes against human serum (transchelation <2%) and its suitability for biological applications. Additionally, on chelation with metal ions, H3glyox exhibits enhanced fluorescence, which was employed to determine the stability constants for Sc­(glyox) in addition to the in-batch UV–vis spectrophotometric titrations; as a proof-of-concept these complexes were used to obtain fluorescence images of live HeLa cells using Sc­(glyox) and Ga­(glyox), confirming the viability of the cells. These initial investigations suggest H3glyox to be a valuable chelator for radiometal-based diagnosis (nuclear and optical imaging) and therapy.