In vivo click reaction between Tc-99m-labeled azadibenzocyclooctyne-MAMA and 2-nitroimidazole-azide for tumor hypoxia targeting

Wenjing Sun; Taiwei Chu

doi:10.1016/j.bmcl.2015.09.004

In vivo click reaction between Tc-99m-labeled azadibenzocyclooctyne-MAMA and 2-nitroimidazole-azide for tumor hypoxia targeting

Bioorg Med Chem Lett. 2015 Oct 15;25(20):4453-6. doi: 10.1016/j.bmcl.2015.09.004. Epub 2015 Sep 5.

Authors

Wenjing Sun¹, Taiwei Chu²

Affiliations

¹ Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
² Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China. Electronic address: twchu@pku.edu.cn.

PMID: 26358160
DOI: 10.1016/j.bmcl.2015.09.004

Abstract

The bioactivity of nitroimidazole in Tc-99m-labeled 2-nitroimidazole, a traditional solid tumor hypoxia-imaging agent for single photon emission computed tomography (SPECT), is reduced by the presence of large ligand and metallic radionuclide, exhibiting lower tumor-to-nontumor ratios. In an effort to solve this general problem, a pretargeting strategy based on click chemistry (strain-promoted cyclooctyne-azide cycloaddition) was applied. The functional click synthons were synthesized as pretargeting components: an azide group linked to 2-nitroimidazole (2NIM-Az) serves for tumor hypoxia-targeting and azadibenzocyclooctyne conjugated with monoamine monoamide dithiol ligand (AM) functions as radiolabeling and binding group to azides in vivo. 2NIM-triazole-MAMA was obtained from in vitro click reaction with a reaction rate constant of 0.98M(-1)s(-1). AM and 2NIM-triazole-MAMA were radiolabeled with Tc-99m. The hypoxia-pretargeting biodistribution was studied in Kunming mice bearing S180 tumor; (99m)Tc-AM and (99m)Tc-triazole-2NIM were used as blank control and conventional control. Compared to the control groups, the pretargeting experiment exhibits the best radio-uptake and retention in tumor, with higher tumor-to-muscle and tumor-to-blood ratios (up to 8.55 and 1.44 at 8h post-(99m)Tc-complex-injection, respectively). To some extent, the pretargeting strategy protects the bioactivity of nitroimidazole and therefore provides an innovative approach for the development of tumor hypoxia-SPECT imaging agents.

Keywords: (99m)Tc-labeling; 2-Nitroimidazole; Pretargeting; SPAAC; Tumor hypoxia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Click Chemistry*
Hypoxia*
Male
Mice
Mice, Inbred Strains
Neoplasms, Experimental / blood
Neoplasms, Experimental / diagnosis*
Organotechnetium Compounds / chemistry
Organotechnetium Compounds / pharmacokinetics*
Radiopharmaceuticals / chemistry
Radiopharmaceuticals / pharmacokinetics*
Tissue Distribution
Tomography, Emission-Computed, Single-Photon

Substances

Organotechnetium Compounds
Radiopharmaceuticals
technetium Tc 99m-2-nitroimidazole-azide
technetium Tc 99m-azadibenzocyclooctyne-MAMA