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

Abstract

With a half-life of 7.45 days, silver-111 (β max 1.04 MeV, E γ 245.4 keV [ I γ 1.24%], E γ 342.1 keV [ I γ 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 NaNO 3 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 [ 111 Ag]Ag + and promising results were obtained.

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

“…Competition Ag + –Cu 2+ measurements were also performed to determine the Cu 2+ -ligand stability constants because the constants of the Ag + -ligand complexes are known. 38 The electronic spectra of the preformed Ag + complex with DO4S, DO3S, DO3SAm, and DO2A2S immediately after the addition of 0.2–4 equiv of Cu 2+ and at equilibrium are shown in Figure S10 . Figures S11–S14 reflect the changes in the spectra over time for each ligand, indicating the slow kinetics of the transmetalation reactions at room temperature.…”

“…The stability constants of the Cu + complexes were calculated using the electrochemical data and the stability constants of the corresponding Cu 2+ complexes, as described in the Supporting Information . It was also assumed that the complex formed between Cu + and each ligand at pH 7 is CuL + because Cu 2+ (see above), Cd 2+ , and Ag + 37 , 38 also form this complex under the same conditions. The results are summarized in Table 8 , together with the calculated pCu + values (pCu + = −log [Cu + ] free ) at different pH values, which indicate that DO4S forms the most stable Cu + complexes.…”

“…In the case of Ag + -DO4S solutions, the metal ion was likely bound by two nitrogen and two sulfur atoms. 38 If the 1 H NMR spectrum of Cu + -DO4S is compared with that of Ag + -DO4S ( Figure S32 ), 38 the metal coordination seems to be different because the signals change in shape and position.…”

“…The Cu + -DO2A2S NMR spectra are similar to those obtained for Ag + -DO2A2S ( Figure S35 ), but signals are narrower when Cu + is coordinated, which might indicate that the cuprous complex is characterized by a slowed-down fluxional interconversion compared to the Ag + one. 38 …”

“…The constants for ligand protonation, Cu 2+ hydroxo species, and, in the case of the competition titrations, also the Ag + complexes were taken from the literature. 37 , 38 , 62…”