Novel Radioiodinated and Radiofluorinated Analogues of FT-2102 for SPECT or PET Imaging of mIDH1 Mutant Tumours

Abstract

Isocitrate dehydrogenases (IDHs) are metabolic enzymes commonly mutated in human cancers (glioma, acute myeloid leukaemia, 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, mIDHs have emerged as highly promising therapeutic targets, and several mIDH specific inhibitors have been developed. However, the evaluation of mIDH status, currently performed 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 noninvasive single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging of mIDH1 up- and dysregulation in tumours. Nonradiolabelled 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 radio-iododemetallation and copper-mediated radiofluorination, respectively. 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.

Mutated Isocitrate Dehydrogenase (mIDH) as Target for PET Imaging in Gliomas

“…In the same work, the potency of the corresponding non-labeled compounds was studied. In line with the above findings, the structural modification resulted in no change in the potency for the iodinated analog and only a modest increase in the biochemical IC 50 values (from 5 to 23 nM for IDH1 R132H or 178 nM to 579 nM for IDH1 R132C ) for the fluorinated analog [ 85 ]. The authors also evaluated the corresponding ( R )-methyl enantiomers, which inhibited IDH1 R132H with at least 30-fold lower potency ( Table 4 ), consistent with the suggested role of the ( S )-methyl substituted benzylic linker for the bioactive inhibitor conformation described above.…”

“…Indeed, during lead optimization, neither replacement of the 6-chloro substituent in compound 4 by fluorine, nor introduction of an additional 7-fluoro substituent in compound 5 or FT-2102 had major adverse effects on the biochemical or cellular potencies against IDH1 R132H and IDH1 R132C (≤2-fold increase in IC 50 values, Table 4 ), and the respective analogs were mainly omitted due to low solubility [ 83 , 84 ]. Accordingly, the first and so far only radiolabeled quinolinone-based inhibitors were developed by replacing the 6-chloro substituent in FT-2102 with fluorine-18 or iodine-125 [ 85 ]. In the same work, the potency of the corresponding non-labeled compounds was studied.…”

“…All four analogs had no appreciable effect on the corresponding wildtype enzymes, with IC 50 values of >10 µM for both IDH1 and IDH2. In addition, the radiolabeled isotopologs of the more potent ( S )-methyl enantiomers ( Figure 9 C) were found to be stable for at least two hours when incubated in saline or buffer solutions at room temperature or in mouse serum at 37 °C [ 85 ]. While further biological evaluation of both radiolabeled inhibitors is pending, these preliminary results support the notion that quinolinone-based inhibitors may be a useful starting point for tracer development.…”

“…In addition, key hydrophobic interactions of the inhibitors with the protein are indicated in turquoise. ( C ) Structure of radiolabeled mIDH inhibitors, with the radiolabels indicated in red [ 85 ].…”

“… a IC 50 values for biochemical assays with IDH1 R132H homodimers, compiled from [ 83 , 84 , 85 ]; b 7 ; c 6 ; d 5 ; e FT-2102 (Olutasidenib); f 8 ; g 4 . …”