Chelation in One Fell Swoop: Optimizing Ligands for Smaller Radiometal Ions

Abstract

[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.

Amyloid β-binding Bifunctional Chelators with Favorable Lipophilicity for 64Cu PET Imaging in Alzheimer’s Disease

“…These pM values could be used as a direct estimate of the ligand-metal affinity and a comparison for metal affinity among difference ligands. 43,48,49 In this work, the calculated pCu values for YW-7 and YW-14 are both 10.8 at pH 7.4, comparable to that of the strong chelating agent DTPA (diethylenetriaminepentaacetic acid), which is 10.7 at pH 7.4, indicating that our BFCs have high Cu(II) binding affinity. (Figure 7).…”

Benzothiazole Carboxylate Diester Bifunctional Chelators for 64Cu PET Imaging in Alzheimer’s Disease

“…The concentrations of free Cu(II) (pM =−log[Munchelated]) at a specific pH value and total ion concentration can be calculated from the solution speciation diagrams, and the calculated pCu values for YW-1 and YW-13 are 11.3 and 12.4 at pH 7.4, respectively, comparable to the value of 10.7 at pH 7.4 for the strong chelating agent DTPA (diethylenetriaminepentaacetic acid), indicating that our BFCs chelate strongly with Cu(II) ion. 34,45,46 YW-1 Species Distribution EPR spectra of copper complexes. To further characterize the copper complexes of ligands, their X-band EPR spectra were recorded in frozen glasses at 77 K. The copper complexes were prepared right before the EPR experiment by reacting ligand with 0.8 equivalent of Cu(ClO4)2•6H2O.…”

Metal ion size profoundly affects H3glyox chelate chemistry

“…29 There are no signicant differences in the bond lengths for the calculated cis [Lu(glyox)(H 2 O) 2 ] complex (Fig. 2D 29 Due to the rigid and distorted planar structure of the ligand, 16 the largest of the three metal ions studied here, Lu 3+ , is exposed to coordination from solvent molecules. Hence, a lesser kinetic inertness of the Lu 3+ -H 3 glyox complex can be predicted from the incorporation of the two cis or trans water molecules completing the Lu 3+ -H 3 glyox coordination sphere.…”

“…ionic size of Lu 3+ (0.86Å) as compared to smaller Ga 3+ (0.62Å) ion, the Lu 3+ ion does not t well in the cavity of the ligand and forms an asymmetric complex. 16…”

“…15 Previously, we reported a versatile bisoxine hexadentate chelator, H 3 glyox (Chart 1); its metal complexes (Sc 3+ , Ga 3+ and In 3+ ) displayed excellent thermodynamic stability in solution and against in vitro human serum challenge. 16 Rapid radiolabeling of [ 44 Sc]Sc 3+ , [ 68 Ga]Ga 3+ and [ 111 In]In 3+ at ambient conditions (RT, 15 min, pH 7) was observed with high specic activity and quantitative yields. Herein, we investigate the complexation ability of H 3 glyox with the divalent metal ions (Mn 2+ and Cu 2+ ) and trivalent metal ion (Lu 3+ ) to gauge the effect of metal ion size, oxidation state and varying coordination preferences on the sequestering capabilities of H 3 glyox.…”