Design and synthesis of a new bifunctional chelating agent: Application for Al ¹⁸F/¹⁷⁷Lu complexation

Theranostic and personalized medicine are blooming strategies to improve oncologic patients' health care and facilitate early treatment. While ¹⁸F-radiochemistry for theranostic application is attractive due to its imaging properties, combining diagnosis by positron emission tomography (PET) via aluminum-fluoride-18 and β^- therapy with lutetium-177 is relevant. Nevertheless, it requires the use of two different chelating agents, which are NOTA and DOTA for aluminum-fluoride-18 and lutetium-177 radiolabeling, respectively. To overcome this issue, we propose herein the synthesis of a new hybrid chelating agent named NO2A-AHM, which can be labeled with different types of emitters (β⁺, β^- and γ) using the mismatched Al¹⁸F/¹⁷⁷Lu pair. NO2A-AHM, is based on a hydrazine moiety functionalized by a NOTA cycle, a chelating arm, and a linker with a maleimide function. This design is chosen to increase the flexibility and allow the formation of 5 up to 7 coordination bonds with metal ions. Moreover, this agent can be coupled to targeting moieties containing a thiol function, such as peptides, to increase selectivity towards specific cancer cells. Experimental complexation and computational chemistry studies are performed to confirm the capacity of our chelating agent to label both aluminum-fluoride and lutetium using molecular modeling approaches at Density Functional Theory (DFT) level. The proof of concept of the ability of NO2A-AHM to complex both aluminum-fluoride-18, for PET imaging applications, and lutetium-177 for radiotherapy has shown encouraging results which is prominent for the development of a fully consistent theranostic approach.