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Open Access 20-11-2023 | Glioma | Original Article

Radiosynthesis and biological evaluation of [18F]AG-120 for PET imaging of the mutant isocitrate dehydrogenase 1 in glioma

Authors: Thu Hang Lai, Barbara Wenzel, Sladjana Dukić-Stefanović, Rodrigo Teodoro, Lucie Arnaud, Aurélie Maisonial-Besset, Valérie Weber, Rareş-Petru Moldovan, Sebastian Meister, Jens Pietzsch, Klaus Kopka, Tareq A. Juratli, Winnie Deuther-Conrad, Magali Toussaint

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 4/2024

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Abstract

Glioma are clinically challenging tumors due to their location and invasiveness nature, which often hinder complete surgical resection. The evaluation of the isocitrate dehydrogenase mutation status has become crucial for effective patient stratification. Through a transdisciplinary approach, we have developed an 18F-labeled ligand for non-invasive assessment of the IDH1R132H variant by using positron emission tomography (PET) imaging. In this study, we have successfully prepared diastereomerically pure [18F]AG-120 by copper-mediated radiofluorination of the stannyl precursor 6 on a TRACERlab FX2 N radiosynthesis module. In vitro internalization studies demonstrated significantly higher uptake of [18F]AG-120 in U251 human high-grade glioma cells with stable overexpression of mutant IDH1 (IDH1R132H) compared to their wild-type IDH1 counterpart (0.4 vs. 0.013% applied dose/µg protein at 120 min). In vivo studies conducted in mice, exhibited the excellent metabolic stability of [18F]AG-120, with parent fractions of 85% and 91% in plasma and brain at 30 min p.i., respectively. Dynamic PET studies with [18F]AG-120 in naïve mice and orthotopic glioma rat model reveal limited blood-brain barrier permeation along with a low uptake in the brain tumor. Interestingly, there was no significant difference in uptake between mutant IDH1R132H and wild-type IDH1 tumors (tumor-to-blood ratio[40−60 min]: ~1.7 vs. ~1.3). In conclusion, our preclinical evaluation demonstrated a target-specific internalization of [18F]AG-120 in vitro, a high metabolic stability in vivo in mice, and a slightly higher accumulation of activity in IDH1R132H-glioma compared to IDH1-glioma. Overall, our findings contribute to advancing the field of molecular imaging and encourage the evaluation of [18F]AG-120 to improve diagnosis and management of glioma and other IDH1R132H-related tumors.
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Metadata
Title
Radiosynthesis and biological evaluation of [18F]AG-120 for PET imaging of the mutant isocitrate dehydrogenase 1 in glioma
Authors
Thu Hang Lai
Barbara Wenzel
Sladjana Dukić-Stefanović
Rodrigo Teodoro
Lucie Arnaud
Aurélie Maisonial-Besset
Valérie Weber
Rareş-Petru Moldovan
Sebastian Meister
Jens Pietzsch
Klaus Kopka
Tareq A. Juratli
Winnie Deuther-Conrad
Magali Toussaint
Publication date
20-11-2023
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Nuclear Medicine and Molecular Imaging / Issue 4/2024
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-023-06515-7