Construction of the Bioconjugate Py-Macrodipa-PSMA and Its In Vivo Investigations with Large 132/135La3+ and Small 47Sc3+ Radiometal Ions

Abstract

To harness radiometals in clinical settings, a chelator forming a stable complex with the metal of interest and targets the desired pathological site is needed. Toward this goal, we previously reported a unique set of chelators that can stably bind to both large and small metal ions, via a conformational switch. Within this chelator class, py-macrodipa is particularly promising based on its ability to stably bind several medicinally valuable radiometals including large ^132/135La³⁺, ²¹³Bi³⁺, and small ⁴⁴Sc³⁺. Here, we report a 10-step organic synthesis of its bifunctional analogue py-macrodipa-NCS, which contains an amine-reactive -NCS group that is amenable for bioconjugation reactions to targeting vectors. The hydrolytic stability of py-macordipa-NCS was assessed, revealing a half-life of 6.0 d in pH 9.0 aqueous buffer. This bifunctional chelator was then conjugated to a prostate-specific membrane antigen (PSMA)-binding moiety, yielding the bioconjugate py-macrodipa-PSMA, which was subsequently radiolabeled with large ^132/135La³⁺ and small ⁴⁷Sc³⁺, revealing efficient and quantitative complex formation. The resulting radiocomplexes were injected into mice bearing both PSMA-expressing and PSMA-non-expressing tumor xenografts to determine their biodistribution patterns, revealing delivery of both ^132/135La³⁺ and ⁴⁷Sc³⁺ to PSMA+ tumor sites. However, partial radiometal dissociation was observed, suggesting that py-macrodipa-PSMA needs further structural optimization.

Keywords: Anticancer agents; Chelate; PSMA; Radiopharmaceuticals; Rare earth.

Figure 1.

Schematic representation of a metal-chelate-based bioconjugate used for nuclear medicine. Reproduced from ref [22]. The targeting vector can be a small-molecule, peptide, antibody, polysaccharide, lipid, or nanoparticle.

Figure 2.

Structures of Ligands Discussed in This Work.

Figure 3.

The hydrolysis of py-macrodipa-NCS at pH 9.0 and RT. The intact compound percentage was plotted versus reaction time and fitted into an exponential decay model.

Figure 4.

Bar graph of biodistribution analysis 2 hours post injection of [^132/135La]La³⁺–py-macrodipa-PSMA (n = 5), [^132/135La]La³⁺–citrate (n = 4), [⁴⁷Sc]Sc³⁺–py-macrodipa-PSMA (n = 5) and [⁴⁷Sc]Sc³⁺–citrate (n = 4) in mice bearing both the PSMA+ and PSMA– tumor xenografts.

Scheme 1.

Synthetic Route to py-macrodipa-NCS.