Copper Coordination Chemistry of Sulfur Pendant Cyclen Derivatives: An Attempt to Hinder the Reductive-Induced Demetalation in 64/67Cu Radiopharmaceuticals.

Marianna Tosato,Marco Dalla Tiezza,André Alker,Valerio Di Marco,Nóra V May,Christian Vaccarin,Helmut Mäcke,Laura Orian,Abdirisak Ahmed Isse,Marco Verona,Sonia Nardella,Paolo Pastore

doi:10.1021/acs.inorgchem.1c01550

Abstract

The Cu2+ complexes formed by a series of cyclen derivatives bearing sulfur pendant arms, 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-10-acetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), and 1,7-bis[2-(methylsulfanyl)ethyl]-4,10-diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S), were studied in aqueous solution at 25 °C from thermodynamic and structural points of view to evaluate their potential as chelators for copper radioisotopes. UV–vis spectrophotometric out-of-cell titrations under strongly acidic conditions, direct in-cell UV–vis titrations, potentiometric measurements at pH >4, and spectrophotometric Ag+–Cu2+ competition experiments were performed to evaluate the stoichiometry and stability constants of the Cu2+ complexes. A highly stable 1:1 metal-to-ligand complex (CuL) was found in solution at all pH values for all chelators, and for DO2A2S, protonated species were also detected under acidic conditions. The structures of the Cu2+ complexes in aqueous solution were investigated by UV–vis and electron paramagnetic resonance (EPR), and the results were supported by relativistic density functional theory (DFT) calculations. Isomers were detected that differed from their coordination modes. Crystals of [Cu(DO4S)(NO3)]·NO3 and [Cu(DO2A2S)] suitable for X-ray diffraction were obtained. Cyclic voltammetry (CV) experiments highlighted the remarkable stability of the copper complexes with reference to dissociation upon reduction from Cu2+ to Cu+ on the CV time scale. The Cu+ complexes were generated in situ by electrolysis and examined by NMR spectroscopy. DFT calculations gave further structural insights. These results demonstrate that the investigated sulfur-containing chelators are promising candidates for application in copper-based radiopharmaceuticals. In this connection, the high stability of both Cu2+ and Cu+ complexes can represent a key parameter for avoiding in vivo demetalation after bioinduced reduction to Cu+, often observed for other well-known chelators that can stabilize only Cu2+.

Highlights

A flourished number of researches have been conducted during the past decades to develop radiopharmaceuticals for noninvasive imaging and treatment of tumors
To obtain site-specific delivery of the emitted radiation, the radioisotopes must be firmly coordinated by a bifunctional chelator (BFC) appended to a tumor-targeting biomolecule through a covalent linkage.[10−12] If the radionuclide is released in vivo from the BFC, high background activity levels are detected, which limit target visualization under diagnostic imaging, and an unintended radiation burden occurs on healthy tissues.[13]
To evaluate the potential of the proposed ligands as BFCs for 64/67Cu-based radiopharmaceuticals, we have investigated their Cu2+ and Cu+ complexes from thermodynamic and structural points of view

Summary

Introduction

A flourished number of researches have been conducted during the past decades to develop radiopharmaceuticals for noninvasive imaging and treatment of tumors. Copper has received much interest because it possesses several radioisotopes (copper-60, copper-61, copper-62, copper-64, and copper-67) with half-life and emission properties suitable for diagnostic and therapeutic applications.[1−3] Copper-64 (64Cu, t1/2 12.7 h) is undoubtedly the most versatile because its unique decay profile, which combines electron capture (IEC 43%), β+ (Iβ+ 18%, Eβ+,max 655 keV) and β− emission (Iβ− 39%, Eβ−,max 573 keV), makes it suitable for positron emission tomography (PET) imaging and, in principle, radiotherapy by using the same radiopharmaceutical.[4−6] 64Cu can provide a matched PET imaging pair with the pure β− emitter copper-67 (67Cu, t1/2 61.9 h, β− 100%, Eβ−,max 141 keV).[7,8] The theranostic approach of using both 64Cu and 67Cu can allow low-dose scouting scans to obtain dosimetry information, followed by higher dose therapy in the same patient, taking a major step toward personalized medicine.[9]. Fast complexation under mild conditions is crucial for allowing the use of heat- and pH-sensitive biovectors.[10,14,15]

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Conclusion