Novel CYP11B-ligand [\(^{123/131}\)I]IMAZA as promising theranostic tool for adrenocortical tumors: comprehensive preclinical characterization and first clinical experience
Zitieren Sie bitte immer diese URN: urn:nbn:de:bvb:20-opus-265606
- Purpose Adrenal tumors represent a diagnostic and therapeutic challenge. Promising results have been obtained through targeting the cytochrome P450 enzymes CYP11B1 and CYP11B2 for molecular imaging, and [\(^{123/131}\)I]iodometomidate ([\(^{123/131}\)I]IMTO) has even been successfully introduced as a theranostic agent. As this radiopharmaceutical shows rapid metabolic inactivation, we aimed at developing new improved tracers. Methods Several IMTO derivatives were newly designed by replacing the unstable methyl ester by different carboxylicPurpose Adrenal tumors represent a diagnostic and therapeutic challenge. Promising results have been obtained through targeting the cytochrome P450 enzymes CYP11B1 and CYP11B2 for molecular imaging, and [\(^{123/131}\)I]iodometomidate ([\(^{123/131}\)I]IMTO) has even been successfully introduced as a theranostic agent. As this radiopharmaceutical shows rapid metabolic inactivation, we aimed at developing new improved tracers. Methods Several IMTO derivatives were newly designed by replacing the unstable methyl ester by different carboxylic esters or amides. The inhibition of aldosterone and cortisol synthesis was tested in different adrenocortical cell lines. The corresponding radiolabeled compounds were assessed regarding their stability, in vitro cell uptake, in vivo biodistribution in mice, and their binding specificity to cryosections of human adrenocortical and non-adrenocortical tissue. Furthermore, a first investigation was performed in patients with known metastatic adrenal cancer using both [\(^{123}\)I]IMTO and the most promising compound (R)-1-[1-(4-[\(^{123/}\)I]iodophenyl)ethyl]-1H-imidazole-5-carboxylic acid azetidinylamide ([\(^{123}\)I]IMAZA) for scintigraphy. Subsequently, a first endoradiotherapy with [\(^{131}\)I]IMAZA in one of these patients was performed. Results We identified three analogues to IMTO with high-affinity binding to the target enzymes and comparable or higher metabolic stability and very high and specific accumulation in adrenocortical cells in vitro and in vivo. Labeled IMAZA exhibited superior pharmacokinetic and imaging properties compared to IMTO in mice and 3 patients, too. An endoradiotherapy with [\(^{131}\)I]IMAZA induced a 21-month progression-free interval in a patient with rapidly progressing ACC prior this therapy. Conclusion We developed the new radiopharmaceutical [\(^{123/131}\)I]IMAZA with superior properties compared to the reference compound IMTO and promising first experiences in humans.…
Autor(en): | Britta Heinze, Andreas Schirbel, Lukas Nannen, David Michelmann, Philipp E. Hartrampf, Christina Bluemel, Magdalena Schneider, Ken Herrmann, Heribert Haenscheid, Martin Fassnacht, Andreas K. Buck, Stefanie Hahner |
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URN: | urn:nbn:de:bvb:20-opus-265606 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Medizinische Fakultät / Klinik und Poliklinik für Nuklearmedizin |
Sprache der Veröffentlichung: | Englisch |
Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | European Journal of Nuclear Medicine and Molecular Imaging |
ISSN: | 1619-7089 |
Erscheinungsjahr: | 2021 |
Band / Jahrgang: | 49 |
Heft / Ausgabe: | 1 |
Seitenangabe: | 301-310 |
Originalveröffentlichung / Quelle: | European Journal of Nuclear Medicine and Molecular Imaging 2021, 49(1):301-310. DOI: 10.1007/s00259-021-05477-y |
DOI: | https://doi.org/10.1007/s00259-021-05477-y |
PubMed-ID: | https://pubmed.ncbi.nlm.nih.gov/34215922 |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Freie Schlagwort(e): | CYP11B enzymes; adrenal incidentaloma; adrenocortical carcinoma |
Datum der Freischaltung: | 25.07.2022 |
Lizenz (Deutsch): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |