Novel radioiodinated and radiofluorinated analogues of FT-2102 for SPECT or PET imaging of mIDH1 mutant tumours

Isocitrate dehydrogenases (IDH) are metabolic enzymes commonly mutated in human cancers (glioma, acute myeloid leukemia, chondrosarcoma, and intrahepatic cholangiocarcinoma). These mutated variants of IDH (mIDH) acquire a neomorphic activity namely conversion of α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate involved in tumourigenesis. Thus, mIDH have emerged as highly promising therapeutic targets and several mIDH specific inhibitors have been developed. However, the evaluation of the mIDH status, currently assessed by biopsy, is essential for patient stratification and thus treatment and follow-up. We report herein the development of new radioiodinated and radiofluorinated analogues of olutasidenib (FT-2102) as tools for non-invasive single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging of mIDH1 up- and dysregulation in tumours. Non-radiolabelled derivatives 2 and 3 halogenated at position 6 of the quinolinone scaffold were synthesised and tested in vitro for their inhibitory potencies and selectivities in comparison with the lead compound FT-2102. Using a common organotin precursor, (S)-[125I]2 and (S)-[18F]3 were efficiently synthesised by either radioiododemetallation or copper-mediated radiofluorination. Both radiotracers were stable at room temperature in saline or DPBS solution and at 37 °C in mouse serum, allowing future planning of their in vitro and in vivo evaluations in glioma and chondrosarcoma models.