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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

Böhmer, V. I., Szymanski, W., van den Berg, K-O., Mulder, C., Kobauri, P., Helbert, H., van den Born, D., Reeβing, F., Huizing, A., Klopstra, M., Samplonius, D. F., Antunes, I. F., Sijbesma, J. W. A., Luurtsema, G., Helfrich, W., Visser, T. J., Feringa, B. L. & Elsinga, P. H., 21-Jul-2020, In : Chemistry. 12 p.

Research output: Contribution to journalArticleAcademicpeer-review

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 andin vitrostudies, all the way to pre-clinicalin vivoevaluation 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 [Ga-68]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.

Original languageEnglish
Number of pages12
JournalChemistry
Publication statusPublished - 21-Jul-2020

    Keywords

  • cancer, click chemistry, cycloadditions, imaging agents, positron emission tomography, GLUTAMATE-CARBOXYPEPTIDASE-II, MEMBRANE ANTIGEN, CLICK CHEMISTRY, CLINICAL TRANSLATION, PET, INHIBITORS, DESIGN, LIGATION, THERAPY, IMPACT

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