Modular Medical Imaging Agents Based on Azide–Alkyne Huisgen Cycloadditions: Synthesis and Pre‐Clinical Evaluation of (18)F‐Labeled PSMA‐Tracers for Prostate Cancer Imaging

Since the seminal contribution of Rolf Huisgen to develop the [3+2] cycloaddition of 1,3‐dipolar compounds, its azide–alkyne variant has established itself as the key step in numerous organic syntheses and bioorthogonal processes in materials science and chemical biology. In the present study, the copper(I)‐catalyzed azide–alkyne cycloaddition was applied for the development of a modular molecular platform for medical imaging of the prostate‐specific membrane antigen (PSMA), using positron emission tomography. This process is shown from molecular design, through synthesis automation and in vitro studies, all the way to pre‐clinical in vivo evaluation of fluorine‐18‐ labeled PSMA‐targeting ‘F‐PSMA‐MIC’ radiotracers (t(1/2)=109.7 min). Pre‐clinical data indicate that the modular PSMA‐scaffold has similar binding affinity and imaging properties to the clinically used [(68)Ga]PSMA‐11. Furthermore, we demonstrated that targeting the arene‐binding in PSMA, facilitated through the [3+2]cycloaddition, can improve binding affinity, which was rationalized by molecular modeling. The here presented PSMA‐binding scaffold potentially facilitates easy coupling to other medical imaging moieties, enabling future developments of new modular imaging agents.