Sc-HOPO: A Potential Construct for Use in Radioscandium-Based Radiopharmaceuticals

Abstract

Three isotopes of scandium─⁴³Sc, ⁴⁴Sc, and ⁴⁷Sc─have attracted increasing attention as potential candidates for use in imaging and therapy, respectively, as well as for possible theranostic use as an elementally matched pair. Here, we present the octadentate chelator 3,4,3-(LI-1,2-HOPO) (or HOPO), an effective chelator for hard cations, as a potential ligand for use in radioscandium constructs with simple radiolabeling under mild conditions. HOPO forms a 1:1 Sc-HOPO complex that was fully characterized, both experimentally and theoretically. [⁴⁷Sc]Sc-HOPO exhibited good stability in chemical and biological challenges over 7 days. In healthy mice, [^43,47Sc]Sc-HOPO cleared the body rapidly with no signs of demetalation. HOPO is a strong candidate for use in radioscandium-based radiopharmaceuticals.

Figure 1.

Structural scheme for the HOPO ligand and the Sc-HOPO complex with the coordinating oxygen atoms shown in red.

Figure 2.

¹H NMR of HOPO and K[Sc(HOPO)] in D₂O. Corresponding integral regions are highlighted by color.

Figure 3.

⁴⁵Sc NMR of K[Sc(HOPO)] in D₂O. The broad peak (FWHM = 12414 Hz) is consistent with ⁴⁵Sc NMR of other Sc chelates. 0.1 M ScCl₃ in 0.01 M HCl was used as the reference standard for the NMR method.

Figure 4.

Molecular diagram of the Sc-HOPO anion. Hydrogen atoms bound to carbon as well as disordered carbon atoms in the HOPO backbone are omitted for clarity. Atomic displacement parameters are displayed at the 30% probability level.

Figure 5.

¹H NMR of K[Sc(HOPO)] taken at different pH’s in D₂O. pH was measured by pH probe, which introduced H₂O to the sample. Although peak suppression for H₂O was used in the NMR method, the quantity of water was too great for it to be effective. pH was adjusted with K₂CO₃ and DCl. The resultant increase of KCl concentration results in minor chemical shift changes for both the analyte and the solvent peak.

Figure 5.

¹H NMR of K[Sc(HOPO)] taken at different pH’s in D₂O. pH was measured by pH probe, which introduced H₂O to the sample. Although peak suppression for H₂O was used in the NMR method, the quantity of water was too great for it to be effective. pH was adjusted with K₂CO₃ and DCl. The resultant increase of KCl concentration results in minor chemical shift changes for both the analyte and the solvent peak.

Figure 6.

8-coordinate structural scheme of Sc-HOPO (A) and alternative 7-coordinate schemes for Sc-HOPOH in low pH conditions (B and C).

Figure 7.

Optimized equilibrium structures for: A) 8-coordinate complex, B) 7-coordinate structure with outer group protonation, and C) 7-coordinate complex with inner group protonation. All hydrogens are omitted except for the protonated OH’s in complexes B and C, which are designated by green arrows. A dashed line indicates hydrogen bonding.

Figure 8.

The five lowest occupied and five highest unoccupied molecular orbitals energies for the 8-coordinate A (1 in the x-axis) complex, 7-coordinate B (2 in the x-axis) and 7-coordinate C (3 in the x-axis) complexes. Frontier orbital representations for the LUMO and HOMO for each complex are shown.

Figure 9.

Coelution of [⁴⁷Sc]Sc-HOPO with macroscopic, characterized Sc-HOPO. As discussed above, both macroscopic and tracer levels show tailing caused by Sc-HOPOH.

Figure 10.

Stability study of [⁴⁷Sc]Sc-HOPO over the course of 7 days in the presence of 100 μM of EDTA at varying pH (A). Stability of [⁴⁷Sc]Sc-DOTA in the presence of 100 μM EDTA at varying pH (B).

Figure 11.

Stability study of [⁴⁷Sc]Sc-HOPO and [⁴⁷Sc]Sc-DOTA over the course of 7 days in the presence of metal ions. (A) [⁴⁷Sc]Sc-HOPO in the presence of 100 μM of FeCl₂, CuCl₂. MgCl₂ and ZnCl_2. (B) Stability of [⁴⁷Sc]Sc-DOTA in the presence of 100 μM of FeCl₂, CuCl₂. MgCl₂ and ZnCl₂.

Figure 12.

Biodistribution of 10 μCi injections of [⁴⁷Sc]Sc-HOPO in female Balb/c mice at four time points: 10 minutes (A), 1 hour (B), 4 hours (C) and 24 hours (D).

Figure 13:

The standard uptake values for various organs of 100 μCi of [⁴³Sc]Sc-HOPO were taken at 10 minute intervals over the course of the 90 minute scan and each organ was then plotted to create a time activity curve for each organ: Brain (A), Lung (B), Kidney (C), Heart (D) and Liver (E).

Figure 14.

(A) PET/CT static image of a Balb/c mouse 0–10 minutes after injection of [⁴³Sc]Sc-HOPO. (B) PET/CT static image of a Balb/c mouse 4–50 minutes after injection of [⁴³Sc]Sc-HOPO. (C) PET/CT static image of a Balb/c mouse 80–90 minutes after injection of [⁴³Sc]Sc-HOPO. Approximately 100 μCi of [⁴³Sc]Sc-HOPO was injected.

Figure 15.

General thermodynamics cycle used to calculate the change in thermodynamic properties in solution.