Fluorinated Derivatives of AG-881 for Positron Emission Tomography Detection of Mutated Isocitrate Dehydrogenase 1

Background/Objectives: Since 2016, the mutation of isocitrate dehydrogenase 1 (mIDH1) enzymes has become a major molecular marker for glioma classification and diagnosis. Moreover, the recent success of the INDIGO clinical trial on AG-881 (vorasidenib^®), an aminotriazine-based mutated IDH1/2 inhibitor (IC₅₀ = 6 nM/12 nM), validated the need for noninvasive detection of mIDH1 in brain tumors. This work is based on developing a series of novel fluorinated analogues of AG-881 and evaluating their potential in mIDH1 PET detection. Methods: The analogues were tested for their potency and then the best candidate was radiofluorinated and used for in vitro cell uptake studies. Results: Six analogues (6-11) were designed and synthesized, but only compound 6 showed nanomolar inhibitory potency towards mIDH1 (IC₅₀ = 400 nM). Following successful radiofluorination, in vitro cell uptake studies showed no selective accumulation of [¹⁸F]6. Conclusions: This study highlights the critical impact of substituent positioning and halogen substitution within the pyridyl moiety on maintaining inhibitory potency. Further medicinal chemistry research is needed to develop an aminotriazine-based ¹⁸F-radiolabeled mIDH1 ligand.