Thwarting Isomerization through Rigidity: A Promising HBED Derivative for the Chelation of Gallium-68

High Resolution Image Download MS PowerPoint Slide The hexadentate acyclic ligand, N,N′-di(2-hydroxybenzyl)-(1,2-cyclohexanediamine)-N,N′-diacetic acid (HBCD) designed for the chelation of the positron-emitting radiometal 68 Ga was developed by replacing the flexible ethylenediamine backbone of its parent ligand, N, N ′-di(2-hydroxybenzyl)ethylenediamine- N, N ′-diacetic acid (HBED), with a more rigid cyclohexane diamine scaffold (DACH). This aims to hinder the formation of multiple isomers upon Ga 3+ -complexation as observed in HBED-containing molecules, which could affect the in vivo behavior of 68 Ga-labeled radiopharmaceuticals. To this end, we report the synthesis of HBCD, a comprehensive investigation of its acid–base behavior, its Ga 3+ coordination chemistry, its labeling performances with generator-produced 68 Ga, and the stability of the corresponding radioactive complex in physiological media. Our findings confirm that the DACH scaffold promotes the formation of a hexacoordinated single-isomer Ga 3+ complex. Although Ga 3+ -HBCD resulted less thermodynamically stable than Ga 3+ -HBED, it is by far more stable than the Ga 3+ complex formed with the clinical workhorse DOTA chelator. HBCD demonstrated the ability to bind [ 68 Ga]Ga 3+ under extremely diluted radiochemical conditions ( C L = 10 –6 M, 90 °C, pH 4.5 and 7). Notably, [ 68 Ga][Ga(HBCD)] − shows exceptional stability in biological media. These results position HBCD as a highly attractive chelator for the development of next-generation PET radiotracers, effectively addressing the issue of isomerization in its parent ligand HBED.