001027684 001__ 1027684
001027684 005__ 20250203103451.0
001027684 037__ $$aFZJ-2024-04002
001027684 041__ $$aEnglish
001027684 1001_ $$0P:(DE-Juel1)166419$$aNeumaier, Bernd$$b0$$eCorresponding author$$ufzj
001027684 1112_ $$a25th International Symposium on Radiopharmaceutical Sciences$$cHonolulu, USA$$d2023-05-22 - 2023-05-26$$gISRS2023$$wUSA
001027684 245__ $$a18F-Labelled inhibitors for targeting of IDH1 mutant gliomas
001027684 260__ $$c2023
001027684 3367_ $$033$$2EndNote$$aConference Paper
001027684 3367_ $$2DataCite$$aOther
001027684 3367_ $$2BibTeX$$aINPROCEEDINGS
001027684 3367_ $$2DRIVER$$aconferenceObject
001027684 3367_ $$2ORCID$$aLECTURE_SPEECH
001027684 3367_ $$0PUB:(DE-HGF)6$$2PUB:(DE-HGF)$$aConference Presentation$$bconf$$mconf$$s1719202127_32506$$xAfter Call
001027684 500__ $$aSupported by Helmholtz European Partnership (HEP)
001027684 520__ $$aObjectives: Low grade diffuse gliomas are primary brain tumorscharacterized by the presence of mutations in isocitrate dehydrogen-ase 1 (IDH1), which equip the enzyme with a neomorphic activity thatincreases production of 2-hydroxyglutarate [1]. High concentrations ofthis oncometabolite are thought to interfere with histone methylationand cellular differentiation, thereby promoting gliomagenesis. Inaddition, mutated IDH1 (mIDH1) has been recognized as a keybiomarker for differential diagnosis, since it is not present in themore aggressive glioblastomas. While current approaches for detec-tion of mIDH1 require invasive tissue sampling, positron emissiontomography (PET) with mIDH1-selective probes could allow for non-invasive assessment of the IDH status. Here, we describe thepreparation, radiofluorination and preliminary biological evaluationof two candidate PET tracers derived from the mIDH1-selectiveinhibitor Olutasidenib.Methods: The boronic acid pinacol ester precursor for coppermediated radiofluorination was prepared using para bromoaniline asthe starting material and Ellman’s sulfinamide as chiral auxiliary forthe formation of the desired S-enantiomer. However, due to significantproduction of the undesired R-enantiomer, we ultimately decided toprepare and radiolabel both R- and S-enantiomer in order to comparethem in cellular uptake assays. For radiofluorination, [ 18 F]fluoride wasloaded onto an anion exchange cartridge and eluted with TEAB inMeOH followed by removal of MeOH. An equimolar solution ofradiolabeling precursor and copper mediator in 1,3-dimethyl-2-imidazolidinone was then added and the mixture was stirred in airat 100 °C for 15 minutes, followed by deprotection with 0.3 M NaOH inH2 O at 80°C for 3 minutes. After HPLC-purification and formulation inphysiological saline solution, the radiotracers were subjected to apreliminary evaluation in wildtype and mIDH1-transfected U-87 MGglioma cell lines.Results: The protected (S) and (R) radiolabeling precursors wereproduced in 15 steps and the 18F-labeled R,S-enantiomers 2 and 3 werefurnished in radiochemical yields of 60 ± 11%, radiochemical purities of>99% and molar activities of 102–237 GBq/μmol. Tracers lipophilicity(logD7.4 ) was found to be 2.53 if measured in PBS buffer but negativewhen measured in water (logP). No degradation was observed duringincubation in rat blood plasma at 37°C over 60 minutes. In contrast ifthe tracer was spotted onto silica plates full degradation was observed.Cell uptake experiments revealed a significantly higher uptake intransfected rather than wild type cells for both [ 18F]1 and S-[18 F]2 butwhile 90% of the first could reach the cytoplasm, the latter mostlyremained in the medium, suggesting that it may only partially cross thecellular membrane.Conclusion: Three 18F-labelled mIDH1-selective inhibitors havebeen successfully prepared and shown to exhibit significantly higheruptake into mIDH1-expressing compared to wildtype glioma cells. Apreclinical evaluation will be performed on [ 18 F]1, while furtherexperiments will be conducted on [ 18 F]2 to explain the unexpectedresults and subsequently compare them with the results of [ 18F]3.
001027684 536__ $$0G:(DE-HGF)POF4-5253$$a5253 - Neuroimaging (POF4-525)$$cPOF4-525$$fPOF IV$$x0
001027684 7001_ $$0P:(DE-Juel1)184639$$aCologni, Roberta$$b1$$ufzj
001027684 7001_ $$0P:(DE-Juel1)131824$$aHolschbach, Marcus$$b2$$ufzj
001027684 7001_ $$0P:(DE-Juel1)131810$$aBier, Dirk$$b3$$ufzj
001027684 7001_ $$0P:(DE-Juel1)145614$$aCarloni, Paolo$$b4$$ufzj
001027684 8564_ $$uhttps://juser.fz-juelich.de/record/1027684/files/1-s2.0-S096980512300344X-main.pdf$$yRestricted
001027684 8564_ $$uhttps://juser.fz-juelich.de/record/1027684/files/1-s2.0-S096980512300344X-main.gif?subformat=icon$$xicon$$yRestricted
001027684 8564_ $$uhttps://juser.fz-juelich.de/record/1027684/files/1-s2.0-S096980512300344X-main.jpg?subformat=icon-1440$$xicon-1440$$yRestricted
001027684 8564_ $$uhttps://juser.fz-juelich.de/record/1027684/files/1-s2.0-S096980512300344X-main.jpg?subformat=icon-180$$xicon-180$$yRestricted
001027684 8564_ $$uhttps://juser.fz-juelich.de/record/1027684/files/1-s2.0-S096980512300344X-main.jpg?subformat=icon-640$$xicon-640$$yRestricted
001027684 909CO $$ooai:juser.fz-juelich.de:1027684$$pVDB
001027684 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)166419$$aForschungszentrum Jülich$$b0$$kFZJ
001027684 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)184639$$aForschungszentrum Jülich$$b1$$kFZJ
001027684 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)131824$$aForschungszentrum Jülich$$b2$$kFZJ
001027684 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)131810$$aForschungszentrum Jülich$$b3$$kFZJ
001027684 9101_ $$0I:(DE-588b)5008462-8$$6P:(DE-Juel1)145614$$aForschungszentrum Jülich$$b4$$kFZJ
001027684 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$$x0
001027684 9141_ $$y2024
001027684 920__ $$lyes
001027684 9201_ $$0I:(DE-Juel1)INM-5-20090406$$kINM-5$$lNuklearchemie$$x0
001027684 9201_ $$0I:(DE-Juel1)INM-9-20140121$$kINM-9$$lComputational Biomedicine$$x1
001027684 980__ $$aconf
001027684 980__ $$aVDB
001027684 980__ $$aI:(DE-Juel1)INM-5-20090406
001027684 980__ $$aI:(DE-Juel1)INM-9-20140121
001027684 980__ $$aUNRESTRICTED