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 18F6. 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.
Lai et al. (Thu,) studied this question.