Highly Stable Silver(I) Complexes with Cyclen-Based Ligands Bearing Sulfide Arms: A Step Toward Silver-111 Labeled Radiopharmaceuticals.

Marianna Tosato,Marco Dalla Tiezza,Mattia Asti,Alberto Andrighetto,Raphael Vogel,Laura Orian,Mikael Jensen,Paolo Pastore,Daniel Häussinger,Ulli Köster,Valerio Di Marco

doi:10.1021/acs.inorgchem.0c01405

Abstract

With a half-life of 7.45 days, silver-111 (βmax 1.04 MeV, Eγ 245.4 keV [Iγ 1.24%], Eγ 342.1 keV [Iγ 6.7%]) is a promising candidate for targeted cancer therapy with β– emitters as well as for associated SPECT imaging. For its clinical use, the development of suitable ligands that form sufficiently stable Ag+-complexes in vivo is required. In this work, the following sulfur-containing derivatives of tetraazacyclododecane (cyclen) have been considered as potential chelators for silver-111: 1,4,7,10-tetrakis(2-(methylsulfanyl)ethyl)-1,4,7,10-tetraazacyclododecane (DO4S), (2S,5S,8S,11S)-2,5,8,11-tetramethyl-1,4,7,10-tetrakis(2-(methylsulfanyl)ethyl)-1,4,7,10-tetraazacyclododecane (DO4S4Me), 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). Natural Ag+ was used in pH/Ag-potentiometric and UV–vis spectrophotometric studies to determine the metal speciation existing in aqueous NaNO3 0.15 M at 25 °C and the equilibrium constants of the complexes, whereas NMR and DFT calculations gave structural insights. Overall results indicated that sulfide pendant arms coordinate Ag+ allowing the formation of very stable complexes, both at acidic and physiological pH. Furthermore, radiolabeling, stability in saline phosphate buffer, and metal-competition experiments using the two ligands forming the strongest complexes, DO4S and DO4S4Me, were carried out with [111Ag]Ag+ and promising results were obtained.

Highlights

In the era of precision medicine, targeted radionuclide therapy (TRT) has emerged as a very powerful approach for the treatment of cancer due to its specificity and minimal invasiveness compared to chemotherapy
This strategy relies on a β−, α, or Auger radiation-emitting nuclide bound to a biologically active targeting molecule that selectively accumulates into specific disease sites while sparing surrounding healthy cells.[1−4] In particular, metallic elements provide a large choice of suitable radionuclides, but the stability and the biological safety of radiopharmaceuticals containing such kind of radionuclides must be ensured by the formation of stable complexes with a bifunctional chelator (BFC) coupled to the targeting moiety via a covalent linkage.[5−8] after injection the radiopharmaceutical must deliver the radionuclide to its cellular, molecular, or biological target without any radiometal loss,[9,10] which would result in an unwanted dose to the patient and injury to normal tissues.[11]
Among the large plethora of β−-emitting metal radionuclides that have been proposed for TRT so far, silver-111 (111Ag, t1/2 7.47 days) is regarded to be promising due to its mediumenergy β− particles and its two useful low energy γ-rays (Eγ 245.4 keV [Iγ 1.24%]; Eγ 342.1 keV, [Iγ 6.7%]) suitable for single photon emission computed tomography (SPECT) imaging.[14−18] An additional positive feature is that the β+-emitters silver-103g (t1/2 65.7 min, β+ 27%, EC 73%) or silver-104g (t1/2 69.2 min, β+ 15%, EC 85%)

Summary

■ INTRODUCTION

In the era of precision medicine, targeted radionuclide therapy (TRT) has emerged as a very powerful approach for the treatment of cancer due to its specificity and minimal invasiveness compared to chemotherapy. Appear for the SCH3 protons, and less clearly still two signals with the same ratio appear for the ring methyl protons (0.9 ppm) This feature might be explained by the formation of two conformers in solution, which are not exchanging on the NMR time scale; the alternative hypothesis, that is, that one of the four sulfur atoms is chemically different from the other three, is possible, it is not supported by DFT according to which the chalcogen atoms are equivalent two-bytwo. According to the temperature effect evidenced on the complex formation for DO4S4Me, this ligand might react with Ag+ more slowly than DO4S, so that the addition of a rigid chiral backbone onto the DO4S structure with the intention of increasing its stability may hamper the labeling kinetics at the lowest concentrations. Copper was chosen because of its physiological relevance, whereas Cd2+ was shown to form very stable complexes with cyclen sulfanyl derivatives[37] and it, represented a valuable test check for metal competition studies

■ CONCLUSIONS

■ ACKNOWLEDGMENTS

■ REFERENCES