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 (t1/2 =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.

Oxygen binding and activation by the complexes of PY2- and TPA-appended diphenylglycoluril receptors with copper and other metals.

The copper(I) complexes of diphenylglycoluril basket receptors and , appended with bis(2-ethylpyridine)amine (PY2) and tris(2-methylpyridine)amine (TPA), respectively, and their dioxygen adducts were studied with low-temperature UV-vis and X-ray absorption spectroscopy (XAS). The copper(I) complex of, [.Cu(I)2] or, forms a micro-eta2:eta2 dioxygen complex, whereas the copper(I) complex of, [.Cu(I)2] or, does not form a well defined dioxygen complex, but is oxidized to Cu(II). Dioxygen is bound irreversibly to and the formed complex is stable over time. The coordination geometries of the above complexes were determined by XAS, which revealed that pyridyl groups and amine N-donors participate in the coordination to Cu(I) ions in the complexes of both receptors. The catalytic activities of various metal complexes of and , that were designed as mimics of dinuclear copper enzymes that can activate dioxygen, were investigated. Phenolic substrates that were expected to undergo aromatic hydroxylation, showed oxidative polymerization without insertion of oxygen. The mechanism of this polymerization turns out to be a radical coupling reaction as was established by experiments with the model substrate 2,4-di-tert-butylphenol. In addition to Cu(II), the Mn(III) complex of and the Fe(II) complex of were tested as oxidation catalysts. Oxidation of catechol was observed for the Cu(II) complex of receptor but the other metal complexes did not lead to oxidation.