Click-to-chelate cyclam derivatives bearing 1,2,3-triazole pendants: Synthesis, conjugation, copper(II) complexation and radiolabeling

Click-to-chelate triazole scaffolds provide favorable metal-binding properties together with facile derivatization. For imaging applications, these features are particularly attractive for radiometal-based tracers, which require high thermodynamic stability and kinetic inertness under physiological conditions. In this work, we report the synthesis and coordination behavior of N -alkylated cyclam with 1,2,3-triazole pendants, designed to enable both efficient copper(II) complexation and bioconjugation with targeting vectors. A bis- c (RGDfK)-cyclam conjugate (16) synthetized via this strategy displays an optimal integrin binding (IC 50 = 4 nM). Copper(II) complexation studies revealed the formation of both penta- and hexacoordinated species, corresponding to trans-I and trans-III configurations of the cyclam, respectively. Structural characterization by single-crystal X-ray diffraction confirmed the hexacoordinated geometry of the thermodynamically favored trans-III-[Cu(13)] 2+ complex. The complexes exhibited high resistance to transchelation under challenging biologically relevant conditions (EDTA, BSA, and FBS). Acid-assisted dissociation kinetics followed pseudo-first-order behavior, with half-lives of 49 min for trans-I-[Cu(13)] 2+ and 9.6 h for trans-III-[Cu(13)] 2+ , highlighting the markedly greater stability of the trans-III isomer. Efficient radiolabeling of 13 with copper-64 was achieved within 15 min at 60 °C, and the high stability of the complex [ 64 Cu]Cu-13 was demonstrated after 24 h in the presence of EDTA and in human plasma.