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Amide-based chelators DTPAm, EGTAm and ampam were synthesized to investigate which chelator most ideally coordinates [ nat/203 Pb]Pb 2+ ions for potential radiopharmaceutical applications. 1 H NMR spectroscopy was used to study each metal-ligand complex in the solution state. The 1 H NMR spectrum of [Pb(DTPAm)] 2+ revealed minimal isomerization and fluxional behaviour compared to [Pb(EGTAm)] 2+ and [Pb(ampam)] 2+ , both of which showed fewer spectral changes indicative of less static behaviour. The solid-state coordination properties of each complex were also examined from single crystal structures that were studied by X-ray diffraction (XRD). In the solid-state, octadentate DTPAm coordinated Pb 2+ to form an eight-coordinate hemidirected complex; octadentate EGTAm coordinated Pb 2+ forming a ten-coordinate holodirected complex with a bidentate NO 3 - ion also coordinated to the metal centre; decadentate ampam completely encapsulated the Pb 2+ ion to form a ten-coordinate holodirected complex with a C 2 axis of symmetry. Potentiometric titrations were carried out to assess the thermodynamic stability of each metal-ligand complex. The pM values obtained for [Pb(DTPAm)] 2+ , [Pb(EGTAm)] 2+ and [Pb(ampam)] 2+ were 9.7, 7.2 and 10.2, respectively. The affinity of each chelator for Pb 2+ ions was tested by [ 203 Pb]Pb 2+ radiolabeling studies to evaluate their prospects as chelators for [ 203/212 Pb]Pb 2+ -based radiopharmaceuticals. DTPAm radiolabeled [ 203 Pb]Pb 2+ ions achieving molar activities as high as 3.5 MBq μmol -1 within 15 minutes, at 25 °C, whereas EGTAm and ampam produced lower molar activities of 0.25 MBq μmol -1 within 30 minutes, at 37 °C. EGTAm and ampam were therefore deemed unsuitable for [ 203/212 Pb]Pb 2+ -based radiopharmaceutical applications, while DTPAm warrants further studies.

A family of phosphonate-bearing chelators was synthesized to study their potential in metal-based (radio)pharmaceuticals. Three ligands (H 6 phospa, H 6 dipedpa, H 6 eppy; structures illustrated in manuscript) were fully characterized, including X-ray crystallographic structures of H 6 phospa and H 6 dipedpa. NMR spectroscopy techniques were used to confirm the complexation of each ligand with selected trivalent metal ions. These methods were particularly useful in discerning structural information for Sc 3+ and La 3+ complexes. Solution studies were conducted to evaluate the complex stability of 15 metal complexes. As a general trend, H 6 phospa was noted to form the most stable complexes, and H 6 eppy associated with the least stable complexes. Moreover, In 3+ complexes were determined to be the most stable, and complexes with La 3+ were the least stable, across all metals. Density functional theory (DFT) was employed to calculate structures of H 6 phospa and H 6 dipedpa complexes with La 3+ and Sc 3+ . A comparison of experimental 1 H NMR spectra with calculated 1 H NMR spectra using DFT-optimized structures was used as a method of structure validation. It was noted that theoretical NMR spectra were very sensitive to a number of variables, such as ligand configuration, protonation state, and the number/orientation of explicit water molecules. In general, the inclusion of an explicit second shell of water molecules qualitatively improved the agreement between theoretical and experimental NMR spectra versus a polarizable continuum solvent model alone. Formation constants were also calculated from DFT results using potential-energy optimized structures. Strong dependence of molecular free energies on explicit water molecule number, water molecule configuration, and protonation state was observed, highlighting the need for dynamic data in accurate first-principles calculations of metal-ligand stability constants.

[ 44/47 Sc]Sc 3+ , [ 68 Ga]Ga 3+ , and [ 111 In]In 3+ 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, H 3 glyox, 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)(H 2 O)] and [In(glyox)(H 2 O)] 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 [ 44 Sc]ScCl 3 (RCY > 99%, [L] = 10 -6 M) was fast at room temperature (pH 7 and 10 min). In vitro experiments revealed exceptional stability of both [ 68 Ga]Ga(glyox) and [ 111 In]In(glyox) complexes against human serum (transchelation <2%) and its suitability for biological applications. Additionally, on chelation with metal ions, H 3 glyox 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 H 3 glyox to be a valuable chelator for radiometal-based diagnosis (nuclear and optical imaging) and therapy.

In this study, we present the synthesis and characterization of the octadentate bispidine ligand, H 2 bispox 2 and its complexes with medicinally useful radiometal nuclides ( 111 In 3+ and 177 Lu 3+ ), including their X-ray diffraction single crystal structures with the stable isotopes. 111 InCl 3 radiolabels the ligand quantitatively at ambient conditions ([L] = 10 -5 M, room temperature, pH 7 and 15 min) and the in vitro human serum stability assays demonstrated high stability of the [ 111 In(bispox 2 )] + complex over 5 days. Moreover, the β - emitter 177 Lu radiolabels the ligand at 37 °C in 30 min (pH 8). These initial investigations reveal the potential of the octadentate bispidine ligand H 2 bispox 2 as a useful chelator for 111 In and 177 Lu-based radiopharmaceuticals.

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.

H 4 octapa 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 H 4 octapa directly from EDDA. Crystals of the octa-protonated form of the ligand [H 8 octapa] 4+ 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 1 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)] 2- species in solution, and their stability constants were evaluated by pH-potentiometric competition titrations using [ttha] 6- 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 SmL = 20.10(2), log K DyL = 20.14(3) and log K YbL = 19.90(1)) are similar to the published values for other lanthanides and consequently these initial investigations confirm H 4 octapa as a valuable ligand for Sm(iii), Dy(iii), Yb(iii) and other Ln for application in diagnostic and therapeutic nuclear medicine.