Alternative Chelator for ⁸⁹Zr Radiopharmaceuticals: Radiolabeling and Evaluation of 3,4,3-(LI-1,2-HOPO)

Abstract

Zirconium-89 is an effective radionuclide for antibody-based positron emission tomography (PET) imaging because its physical half-life (78.41 h) matches the biological half-life of IgG antibodies. Desferrioxamine (DFO) is currently the preferred chelator for 89Zr4+; however, accumulation of 89Zr in the bones of mice suggests that 89Zr4+ is released from DFO in vivo. An improved chelator for 89Zr4+ could eliminate the release of osteophilic 89Zr4+ and lead to a safer PET tracer with reduced background radiation dose. Herein, we present an octadentate chelator 3,4,3-(LI-1,2-HOPO) (or HOPO) as a potentially superior alternative to DFO. The HOPO ligand formed a 1:1 Zr-HOPO complex that was evaluated experimentally and theoretically. The stability of 89Zr-HOPO matched or surpassed that of 89Zr-DFO in every experiment. In healthy mice, 89Zr-HOPO cleared the body rapidly with no signs of demetalation. Ultimately, HOPO has the potential to replace DFO as the chelator of choice for 89Zr-based PET imaging agents.

Tripodal tris(hydroxypyridinone) ligands for immunoconjugate PET imaging with 89Zr4+: comparison with desferrioxamine-B

“…Indeed, recently reported stability constant data indicates a preference for 1 : 4 complexes for the Me-AHA complex. 16 We, like others, 16,27 predict that replacing a hexadentate ligand with an octadentate ligand containing eight coordinating O atoms could increase the specific activity, inertness and complex stability of a 89 Zr-labeled immunoconjugate, reducing the bone uptake observed in small animal rodents that is observed for H 3 DFO-immunoconjugates.…”

p-SCN-Bn-HOPO: A Superior Bifunctional Chelator for 89Zr ImmunoPET

“…Figure S.1 shows the variation of bond lengths in these two crystal structures and in the DFT calculated structure of Zr-HOPO (Zr-HOPO calc ). 34 …”

“…39 As we postulated, the HOPO ligand labeled efficiently and 89 Zr-HOPO exhibited equal or superior stability compared to 89 Zr-DFO in all chemical and biological assays. 34 Not only did the 3,4,3-(LI-1,2-HOPO) ligand show tremendous promise in our preliminary evaluation, but even more recently, stability constants for Zr-HOPO were determined to be on the order of log β = 43, the highest recorded for any Zr complex which attests to the superior stability. 40 Therefore, we endeavored to develop a bifunctional variant of the HOPO ligand for further evaluation and application in antibody-based PET imaging.…”

“…34 The development of a bifunctional derivative of the HOPO ligand was the next logical step and led to the design and synthesis of p -SCN-Bn-HOPO. This bifunctional ligand was shown to bind 89 Zr as expected and was evaluated for conjugation to an antibody, radiolabeling of the ligand–antibody complex, and application of the radioimmunoconjugate in vivo.…”

In vivo imaging with antibodies and engineered fragments

“…However, 89 Zr released from DFO accumulates in bone and can presents toxicity issues or obscure imaging of lesions in the bone. Efforts have been made to improve upon the chelating molecule (Deri et al, 2014; Guérard et al, 2014, 2013; Price et al, 2014). Scandium-44 (t 1/2 = 3.9 h) continues to be explored in conjunction with intermediate-sized fragments such as Fabs (Chakravarty et al, 2014), and gallium-68 (t 1/2 = 68 min) is gaining popularity as a label for smaller fragments such as nanobodies and affibodies (Honarvar et al, 2014; Xavier et al, 2013).…”