Development of Radioiodinated Tetrahydropyrazolopyridine Inhibitors Targeting mIDH

ABSTRACT Isocitrate dehydrogenase 1/2 (IDH1/2) mutations are key oncogenic drivers in multiple cancers and represent important diagnostic and therapeutic targets, particularly in glioma and chondrosarcoma. Here, we report the design, synthesis, and in vitro evaluation of iodinated derivatives based on the tetrahydropyrazolopyridine scaffold of the mIDH1 inhibitors SK60 and SK87 . Structure‐guided modification of the halogenated benzyl moiety yielded iodinated analogues SK140 ( 9 ) and SK148 ( 10 ), which demonstrated nanomolar inhibitory potencies against IDH1R132C in vitro, exceeding that of the corresponding fluorinated compounds. Radiolabeling was successfully achieved using iodine‐125 via organotin precursors, affording [ 125 I]SK140 and [ 125 I]SK148 in good radiochemical yields. Both radiotracers exhibited excellent stability in formulation media (ethanol, 0.9% NaCl, and PBS) over 24 h at RT. Collectively, these results demonstrate that iodinated tetrahydropyrazolopyridine derivatives can be efficiently radiolabeled and remain stable under formulation conditions, supporting their further evaluation as potential mIDH1‐targeting radiotracers.