Squaric Acid-Based Radiopharmaceuticals for Tumor Imaging and Therapy.

Targeting vectors bound to a chelator represent a significant fraction of radiopharmaceuticals used nowadays for diagnostic and therapeutic purposes in nuclear medicine. The use of squaramides as coupling units for chelator and targeting vector helps to circumvent the disadvantages of several common coupling methods. This review gives an overview of the use of squaric acid diesters (SADE) as linking agents. It focuses on the conjugation of cyclic chelators, e.g., DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), as well as hybrid chelators like AAZTA5 (6-pentanoic acid-6-amino-1,4-diazepine tetracetic acid) or DATA5m (6-pentanoic acid-6-amino-1,4-diazapine-triacetate) to different targeting vectors, e.g., prostate-specific membrane antigen inhibitors (KuE; PSMAi), fibroblast activation protein inhibitors (FAPi), and monoclonal antibodies (mAbs). An overview of the synthesis, radiolabeling, and in vitro and in vivo behavior of the described structures is given. The unique properties of SADE enable a fast and simple conjugation of chelators to biomolecules, peptides, and small molecules under mild conditions. Furthermore, SA-containing conjugates could not only display similar in vitro characteristics in terms of binding affinity when compared to reference compounds, but may even induce beneficial effects on the pharmacokinetic properties of these radiopharmaceuticals.