N,1,4-Tri(4-alkoxy-2-hydroxybenzyl)-DAZA: efficient one-pot synthesis and labelling with 68Ga for PET liver imaging in ovo†
We report the isolation of a new type of 1,4-diazepan-6-amine (DAZA)-based ligand. Condensation of aldehydes with DAZA gives a novel class of 1,5-diazabicyclo[3.2.1]octanes in nearly quantitative yields. Subsequent reductive cleavage of these bicyclic aminal species with sodium borohydride selectively leads to N,1,4-tri(4-alkoxy-2-hydroxybenzyl)-1,4-diazepan-6-amines (alkoxy = Me: TMeOHB-DAZA; alkoxy = Et: TEtOHB-DAZA) via a unique reductive alkylation reaction in which a substituent is added to the DAZA moiety without the presence of an alkylating agent. Mass spectrometry studies of the intermediates suggest that the mechanism involves insertion of in situ released carbonyl species into an aminal bond to form hemiaminal intermediates, and subsequent reduction. TMeOHB-DAZA and TEtOHB-DAZA are hexadentate ligands suitable for effectively coordinating Ga(III) ions. Chelation of the radionuclide 68Ga was achieved within 5 min at 100 °C. In vitro stability studies in PBS and human serum confirmed the kinetic inertness of the tracers as no 68Ga demetallation was observed over a period of 4 h. Positron emission tomography (PET)/computed tomography (CT) imaging after in ovo administration to incubated ostrich eggs showed a high uptake in the liver, namely 27% (60 min post injection), and subsequent biliary excretion. These results suggest that [68Ga]Ga-TMeOHB-DAZA and [68Ga]Ga-TEtOHB-DAZA have excellent potential as hepatobiliary PET/CT imaging agents.