Synthesis and ⁶⁴Cu-Radiolabeling Strategies of Small Organic Radioconjugates Based on the AMD070 Scaffold

CXCR4 is a transmembrane receptor overexpressed in a large variety of cancer cells. In addition to classical antibody- and peptide-targeting for the development of positron emission tomography (PET) radiopharmaceuticals, this receptor possesses a range of small organic inhibitors that can be exploited. These are based mainly on nitrogen-rich scaffolds, such as AMD070, and cyclic polyamines, such as cyclam, in the AMD3100 skeleton. The latter has been explored as a direct ⁶⁴Cu chelator, but examples of CXCR4 PET imaging with small organic targeting units are still scarce in the literature. Herein, the synthesis of two novel CXCR4-directed radiopharmaceuticals is described, combining the AMD070 scaffold as a targeting unit and bifunctional te1pa macrocycle as a strong ⁶⁴Cu chelator. The synthesis of the conjugates and optimization of ⁶⁴Cu-radiolabeling are presented, opening the way for future in vitro and in vivo studies.