@article {doi:10.1021/acs.inorgchem.2c04123,
	title = {Toward 68Ga and 64Cu Positron Emission Tomography Probes: Is H2dedpa-N,N'-pram the Missing Link for dedpa Conjugation?},
	journal = {Inorg. Chem.},
	volume = {62},
	number = {50},
	year = {2023},
	note = {PMID: 36662237},
	month = {01/2023},
	pages = {20593-20607.  Invited for Forum "Inorganic Chemistry of Radiopharmaceuticals},
	abstract = {<p>H2dedpa-N,N\&prime;-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\&prime;-prpta (H2L2) platform as a simple structural model for its conjugated systems. X-ray crystallography confirmed that the N4O2 coordination sphere provided by the dedpa2\&ndash; 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\&ndash;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\&prime;-pram) and 20.8 (dedpa-N,N\&prime;-prpta) versus 18.5 (DOTA) at identical conditions], and significantly higher for the Cu(II) complexes [pCu = 21.96 (dedpa-N,N\&prime;-pram) and 22.8 (dedpa-N,N\&prime;-prpta) versus 16.2 (DOTA)], which are even more stable than that of the parent ligand dedpa2\&ndash; (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 dedpa2\&ndash; 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\&ndash;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.</p>},
	doi = {10.1021/acs.inorgchem.2c04123},
	url = {https://doi.org/10.1021/acs.inorgchem.2c04123},
	author = {Pena-Bonhome, Celia and Fiaccabrino, Desiree and Rama, Tamara and Fern{\'a}ndez-Pav{\'o}n, Daniel and Southcott, Lily and Zhang, Zhengxing and Lin, Kuo-Shyan and de Blas, Andr{\'e}s and Patrick, Brian O. and Schaffer, Paul and Orvig, Chris and Jaraquemada-Pelaez, Maria de Guadalupe and Rodr{\'\i}guez-Blas, Teresa}
}
