Developing scandium and yttrium coordination chemistry to advance theranostic radiopharmaceuticals

Korey P Carter,Trevor D Lohrey,Tyler A Bailey,Gauthier J.-P Deblonde,Rebecca J Abergel,Dahlia D An,Wayne W Lukens,Katherine M Shield

doi:10.1038/s42004-020-0307-0

Abstract

The octadentate siderophore analog 3,4,3-LI(1,2-HOPO), denoted 343-HOPO hereafter, is known to have high affinity for both trivalent and tetravalent lanthanide and actinide cations. Here we extend its coordination chemistry to the rare-earth cations Sc3+ and Y3+ and characterize fundamental metal–chelator binding interactions in solution via UV-Vis spectrophotometry, nuclear magnetic resonance spectroscopy, and spectrofluorimetric metal-competition titrations, as well as in the solid-state via single crystal X-ray diffraction. Sc3+ and Y3+ binding with 343-HOPO is found to be robust, with both high thermodynamic stability and fast room temperature radiolabeling, indicating that 343-HOPO is likely a promising chelator for in vivo applications with both metals. As a proof of concept, we prepared a 86Y-343-HOPO complex for in vivo PET imaging, and the results presented herein highlight the potential of 343-HOPO chelated trivalent metal cations for therapeutic and theranostic applications.

Highlights

The octadentate siderophore analog 3,4,3-LI(1,2-HOPO), denoted 343-HOPO hereafter, is known to have high affinity for both trivalent and tetravalent lanthanide and actinide cations
The full potential of nuclear medicine may be realized with theranostics, wherein a molecular targeting vector is labeled with both a diagnostic and a therapeutic radionuclide that are utilized for concomitant imaging and treatment[3,4,5,6]
This approach is hindered by the different ionic radii of these elements (CN = 6, 0.62 Å for Ga3+; CN = 8, 0.977 Å for Lu3+; CN = 8, 1.019 Å for Y3+)[7,8], which leads to mismatches in coordination chemistry and varying in vivo behavior[9,10,11]

Summary

Introduction

The octadentate siderophore analog 3,4,3-LI(1,2-HOPO), denoted 343-HOPO hereafter, is known to have high affinity for both trivalent and tetravalent lanthanide and actinide cations. Density functional theory calculations have highlighted structural deformities for 343-HOPO complexes with endogenous metals, which minimizes in vivo competition for the rare-earth cations (Sc3+, Y3+) included in 343HOPO chelates [24].

Results

Conclusion