Developing scandium and yttrium coordination chemistry to advance theranostic radiopharmaceuticals

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 Sc 3+ and Y 3+ and characterize fundamental metal-chelator binding interactions in solution via UV-Vis spectrophotometry, nuclear magnetic resonance spectroscopy, and spectrofluorimetric metalcompetition titrations, as well as in the solid-state via single crystal X-ray diffraction. Sc 3+ and Y 3+ 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 86 Y-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.

Versatile Macrocyclic Platform for the Complexation of [natY/90Y]Yttrium and Lanthanide Ions

“…Thus, the positron emitter 86 Y has been attracting attention over the last few years as a candidate for the design of radiopharmaceuticals for positron emission tomography (PET) due to its versatile half-life (14.74 h) and its well-known chelation chemistry. Moreover, the existence of the β – emitter isotope [ 90 Y]-yttrium allows for the design of theranostic agents, making yttrium an extremely interesting option in nuclear medicine. , To construct a metal-based radiopharmaceutical, a bifunctional chelator is typically chosen, which is basically a chelating ligand provided with a linker capable of conjugation to a targeting vector. , It must be noted that time is of the essence when working with decaying nuclides, so even though kinetic inertness with respect to dissociation is still fundamental, matching the kinetics of formation with the lifetime of the radioisotope is of paramount importance as well. , …”

Hydroxypyridinone-Based Metal Chelators towards Ecotoxicity: Remediation and Biological Mechanisms

“…Moreover, the widely studied compound L27 continues to be evaluated as a chelating agent towards different metal ions and quite recently its binding interaction with rare earths (Sc 3+ (log β ScL = 25.16), Y 3+ (log β YL = 20.76)) [ 84 ], Hf 4+ and Zr 4+ (log β ML > 42, complexes stable between pH 10 and 10 M HCl) [ 85 ], as well as a coordination study (X-ray absorption spectroscopy—XAS, luminescence measurements) with the heaviest element (einsteinium) that can be generated in quantities that enable classical macroscale studies have been performed [ 86 ]. Complexation studies of L28 with Eu 3+ , Zr 4+ and Th 4+ (log β EuL = 29.65, log β ZrL = 57.26 and log β ThL = 47.71) [ 87 ] evidenced the excellent chelating ability of this compound for both trivalent and tetravalent metal ions at the physiological pH.…”

Hydroxypyridinones as a Very Promising Platform for Targeted Diagnostic and Therapeutic Radiopharmaceuticals

“…Recently, Abergel s group used various methods to study the coordination chemistry of 3,4,3-LI(1,2-HOPO) with rare earth cations Sc 3+ and Y 3+ . Their results showed that the binding of Sc 3+ and Y 3+ to 3,4,3-LI(1,2-HOPO) is strong, with high thermodynamic stability and rapid radiolabeling at room temperature, indicating that 3,4,3-LI(1,2-HOPO) may be a promising chelating agent of these two metals for in vivo diagnosis and treat-ment [72]. They also synthesized the octa-dentate ligands 3,4,3-LI(1,2-HOPO) 2 (CAM) 2 and 3,4,3-LI(CAM) 2 (1,2-HOPO) 2 , and studied their thermodynamic and photophysical properties with Eu 3+ and Tb 3+ .…”