001027957 001__ 1027957
001027957 005__ 20240626202013.0
001027957 037__ $$aFZJ-2024-04252
001027957 041__ $$aGerman
001027957 1001_ $$0P:(DE-Juel1)180330$$aEndepols, Heike$$b0$$eCorresponding author$$ufzj
001027957 1112_ $$a62. Jahrestagung der Deutschen Gesellschaft für Nuklearmedizin$$cLeipzig$$d2024-04-10 - 2024-04-13$$gDGN 2024$$wGermany
001027957 245__ $$aDevelopment and preclinical evaluation of radiofluorinated olutasidenib derivatives for non-invasive detection of mutated isocitrate dehydrogenase 1 (mIDH1) in gliomas
001027957 260__ $$c2024
001027957 3367_ $$033$$2EndNote$$aConference Paper
001027957 3367_ $$2DataCite$$aOther
001027957 3367_ $$2BibTeX$$aINPROCEEDINGS
001027957 3367_ $$2DRIVER$$aconferenceObject
001027957 3367_ $$2ORCID$$aLECTURE_SPEECH
001027957 3367_ $$0PUB:(DE-HGF)6$$2PUB:(DE-HGF)$$aConference Presentation$$bconf$$mconf$$s1719398279_10095$$xAfter Call
001027957 520__ $$aZiel/Aim: Mutations of isocitrate dehydrogenase 1 (IDH1) are key biomarkers for glioma classification, but current methods for detection of mutated IDH1 (mIDH1) require invasive tissue sampling. The aim of the present work was to develop radiofluorinated analogs of the mIDH1-selective inhibitor olutasidenib as positron emission tomography (PET) probes for non-invasive detection of mIDH1.Methodik/Methods: Four radiolabeled olutasidenib derivatives were prepared by Cu-mediated radiofluorination of suitable boronic acid pinacol esters or aliphatic radiofluorination under ‘minimalist’ conditions. They were characterized by cellular uptake studies, using U87 glioma cells with a heterozygous IDH1R132H mutation (U87-mIDH1) and the corresponding wildtype cells (U87-WT). In addition, PET imaging in mice with subcutaneous U87-mIDH1 and U87-WT tumors was used to evaluate the in vivo biodistribution and mIDH1-selectivity of the most promising probe. Apart from analyzing semiquantitative SUV, kinetic modeling was performed using PMOD.Ergebnisse/Results: All four probes effectively inhibited mIDH1, with [F-18]mIDH-138 displaying the highest potency (IC50=103 nM). [F-18]mIDH-138 also showed significantly higher cellular accumulation in U87-mIDH1 compared to U87-WT cells, while none of the other probes exhibited preferential in vitro uptake into U87-mIDH1 cells. PET imaging demonstrated a good in vivo stability and low non-specific uptake of [F-18]mIDH-138, but also revealed significantly higher uptake into U87-WT compared to U87-mIDH1 tumors. This was confirmed by kinetic modeling, which showed significantly higher total and specific distribution volumes as well as binding potentials (BPND) in U87-WT tumors.Schlussfolgerungen/Conclusions: In conclusion, the results indicate that mIDH1-selective inhibition may not directly correlate with mIDH1-selective target engagement and that in vivo engagement of wildtype and mutated IDH1 may be governed by factors that are not faithfully reproduced by in vitro assays, both of which could complicate development of PET probes.
001027957 536__ $$0G:(DE-HGF)POF4-5253$$a5253 - Neuroimaging (POF4-525)$$cPOF4-525$$fPOF IV$$x0
001027957 7001_ $$0P:(DE-Juel1)156407$$aSchneider, Daniela$$b1$$ufzj
001027957 7001_ $$0P:(DE-Juel1)184639$$aCologni, Roberta$$b2$$ufzj
001027957 7001_ $$0P:(DE-Juel1)175142$$aNeumaier, Felix$$b3$$ufzj
001027957 7001_ $$0P:(DE-Juel1)131810$$aBier, Dirk$$b4$$ufzj
001027957 7001_ $$0P:(DE-Juel1)131824$$aHolschbach, Marcus$$b5$$ufzj
001027957 7001_ $$0P:(DE-Juel1)166419$$aNeumaier, Bernd$$b6$$ufzj
001027957 909CO $$ooai:juser.fz-juelich.de:1027957$$pVDB
001027957 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)180330$$aForschungszentrum Jülich$$b0$$kFZJ
001027957 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)156407$$aForschungszentrum Jülich$$b1$$kFZJ
001027957 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)184639$$aForschungszentrum Jülich$$b2$$kFZJ
001027957 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)175142$$aForschungszentrum Jülich$$b3$$kFZJ
001027957 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)131810$$aForschungszentrum Jülich$$b4$$kFZJ
001027957 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)131824$$aForschungszentrum Jülich$$b5$$kFZJ
001027957 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)166419$$aForschungszentrum Jülich$$b6$$kFZJ
001027957 9131_ $$0G:(DE-HGF)POF4-525$$1G:(DE-HGF)POF4-520$$2G:(DE-HGF)POF4-500$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$9G:(DE-HGF)POF4-5253$$aDE-HGF$$bKey Technologies$$lNatural, Artificial and Cognitive Information Processing$$vDecoding Brain Organization and Dysfunction$$x0
001027957 9141_ $$y2024
001027957 920__ $$lyes
001027957 9201_ $$0I:(DE-Juel1)INM-5-20090406$$kINM-5$$lNuklearchemie$$x0
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001027957 980__ $$aI:(DE-Juel1)INM-5-20090406
001027957 980__ $$aUNRESTRICTED