Improved synthesis of the bifunctional chelator p-SCN-Bn-HOPO.

The bifunctional ligand p-SCN-Bn-HOPO, which has four 1,2-hydroxypyridinone groups on a spermine backbone with an isothiocyanate linker, has been shown to be an efficient and stable chelator for Zr(iv) and, more importantly, the radioisotope 89Zr for use in radiolabeling antibodies for positron emission tomography (PET) imaging. Previous studies of 89Zr-HOPO-trastuzumab in mice showed low background, good tumor to organ contrast, and very low bone uptake which show p-SCN-Bn-HOPO to be an important next-generation bifunctional chelator for radioimmunoPET imaging with 89Zr. However, the reported synthesis of p-SCN-Bn-HOPO involves nine steps and multiple HPLC purifications with an overall yield of about 1.

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

Zirconium-89 has an ideal half-life for use in antibody-based PET imaging; however, when used with the chelator DFO, there is an accumulation of radioactivity in the bone, suggesting that the (89)Zr(4+) cation is being released in vivo. Therefore, a more robust chelator for (89)Zr could reduce the in vivo release and the dose to nontarget tissues. Evaluation of the ligand 3,4,3-(LI-1,2-HOPO) demonstrated efficient binding of (89)Zr(4+) and high stability; therefore, we developed a bifunctional derivative, p-SCN-Bn-HOPO, for conjugation to an antibody.