Synthesis and Structural Analysis of 1,4,7,10‐Tetraazacyclododecane‐1,4,7,10‐­tetraazidoethylacetic Acid (DOTAZA) Complexes

Abstract

Herein, we present the synthesis and structural analysis of metal complexes of enantiomerically pure 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraazidoethylacetic acid (DOTAZA). DOTAZA is a new tunable analog of DOTA, a clinically approved chelator for various pharmaceutically relevant metal ions. In this work, we investigate the complexation chemistry of DOTAZA and report the crystal structures of a number of complexes with pharmaceutically relevant metal ions such as Gd3+ [magnetic resonance imaging (MRI)], Eu3+ (luminescence spectroscopy), Y3+ [positron emission tomography (PET)], In3+ [single‐photon‐emission computed tomography (SPECT)], and Na+. These structures provide useful information for imaging applications and demonstrate the potential of DOTAZA to form stable complexes. Owing to its clickable azide functionalities, it may be used for the development of tailored imaging reagents that retain the positive complexation chemistry of the parent compound DOTA.

Radioactive Main Group and Rare Earth Metals for Imaging and Therapy

“…Indium-111 radiotracers are a prime example of indiscriminate use of DOTA. Despite the need for elevated radiolabeling temperatures and lower log K ML and pM values than DTPA, DOTA continues to be applied to 111 In radiopharmaceuticals. ,− Although no [In­(DOTA)] − crystal structure has been reported, based on a number of closely related DOTA analogues (In­[DO3A], In­[DOTA-AA], and In­[DOTAZA] − ), the In 3+ center likely adopts square antiprismatic geometry. − Compared to other macrocyclic ligands, the size of In 3+ is best suited to DOTA, which was found to form slightly more stable complexes (log K ML = 23.9) than extended cyclen analogues [13]­aneN 4 (TRITA; 1,4,7,10-tetraazacyclotridecane- N,N′,N″N′″ -tetraacetic acid; Figure E) and [14]­aneN 4 (TETA; Figure F) (log K ML = 23.00 and 21.89, respectively) . Smaller macrocycles have also been studied with In 3+ ; however, the low coordination number and nonideal ring size, revealed through crystal structures, , should deter future use of small macrocycles with 111 In 3+ .…”

Optimization of Artificial Siderophores as 68Ga-Complexed PET Tracers for In Vivo Imaging of Bacterial Infections

“…Compared to previous siderophore-PET probes, the separation of iron and PET-tracer binding sites allows us to also accommodate other metal cations (e.g., 111 In or 64 Cu) that might fit less well into the siderophore binding site that was optimized for iron. The versatile scaffold, well-amenable to further modifications, 34,63 allows us to fine-tune properties and/or to introduce additional functionalities such as an antibiotically active moiety to obtain full bacteria-targeted theranostics. Indeed, a structural optimization is indicated to further improve parameters such as tracer stability in vivo or enrichment in bacteria.…”

Nonradioactive Cell Assay for the Evaluation of Modular Prostate-Specific Membrane Antigen Targeting Ligands via Inductively Coupled Plasma Mass Spectrometry

“…In this context, the macrocyclic compound 1,4,7,10-tetraazadodecyl-1,4,7,10-tetraacetic acid (DOTA) is a well-known chelator with favorable complex chemistry for a number of clinically relevant metal cations (e.g. 68 Ga 3+ , 111 In 3+ , Gd 3+ , 177 Lu 3+ , and 225 Ac 3+ ). − Hence, DOTA-conjugated targeting ligands are currently intensively used as tracers for application in PET, SPECT, MRI, and radiotherapy. ,,,− …”