Toward Ga and Cu Positron Emission Tomography Probes: Is Hdedpa-,'-pram the Missing Link for dedpa Conjugation?

Hdedpa-,'-pram (HL), a new chelator derived from the hexadentate ligand 1,2-bis[[(6-carboxypyridin-2-yl)methyl]amino]ethane (Hdedpa), 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 Ga- and Cu-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 Hdedpa-,'-prpta (HL) platform as a simple structural model for its conjugated systems. X-ray crystallography confirmed that the NO coordination sphere provided by the dedpa 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-,'-pram) and 20.8 (dedpa-,'-prpta) versus 18.5 (DOTA) at identical conditions], and significantly higher for the Cu(II) complexes [pCu = 21.96 (dedpa-,'-pram) and 22.8 (dedpa-,'-prpta) versus 16.2 (DOTA)], which are even more stable than that of the parent ligand dedpa (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 into tertiary amines, whereby the architecture of the new HL 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 ([Ga]Ga and [Cu]Cu) was observed within 15 min at room temperature with concentrations as low as 10 M. Furthermore, serum stability studies confirmed a high radiochemical stability of all systems and therefore confirmed HL as a promising and versatile chelator for further radiopharmaceutical studies.