177-Lu-DOTA-cG250(Ludwig Institute for Cancer Research)

H₂dedpa-N,N'-pram (H₂L¹), a new chelator derived from the hexadentate ligand 1,2-bis[[(6-carboxypyridin-2-yl)methyl]amino]ethane (H₂dedpa), which incorporates 3-propylamine chains anchored to the secondary amines of the ethylenediamine core of the latter, has emerged as a very promising scaffold for preparing ⁶⁸Ga- and ⁶⁴Cu-based positron emission tomography probes. This new platform is cost-effective and easy to prepare, and the two pendant primary amines make it versatile for the preparation of bifunctional chelators by conjugation and/or click chemistry. Reported herein, we have also included the related H₂dedpa-N,N'-prpta (H₂L²) platform as a simple structural model for its conjugated systems. X-ray crystallography confirmed that the N₄O₂ coordination sphere provided by the dedpa^2- core is maintained at both Ga(III) and Cu(II). The complex formation equilibria were deeply investigated by a thorough multitechnique approach with potentiometric, NMR spectrometric, and UV-vis spectrophotometric titrations, revealing effective chelation. The thermodynamic stability of the Ga(III) complexes at physiological relevant conditions is slightly higher than that of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), the common and clinically approved chelator used in the clinic [pGa = 19.5 (dedpa-N,N'-pram) and 20.8 (dedpa-N,N'-prpta) versus 18.5 (DOTA) at identical conditions], and significantly higher for the Cu(II) complexes [pCu = 21.96 (dedpa-N,N'-pram) and 22.8 (dedpa-N,N'-prpta) versus 16.2 (DOTA)], which are even more stable than that of the parent ligand dedpa^2- (pCu = 18.5) and that of 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) (pCu = 18.5). This high stability found for Cu(II) complexes is related to the conversion of the secondary amines of the ethylenediamine core of dedpa^2- into tertiary amines, whereby the architecture of the new H₂L¹ chelator is doubly optimal in the case of this metal ion: high accessibility of the primary amine groups and their incorporation via the secondary amines, which contributes to a significant increase in the stability of the metal complex. Quantitative labeling of both chelators with both radionuclides ([⁶⁸Ga]Ga³⁺ and [⁶⁴Cu]Cu²⁺) was observed within 15 min at room temperature with concentrations as low as 10^-5 M. Furthermore, serum stability studies confirmed a high radiochemical in vitro stability of all systems and therefore confirmed H₂L¹ as a promising and versatile chelator for further radiopharmaceutical in vivo studies.