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Peer-reviewedCC BY-NC-NDJournal of labelled compounds & radiopharmaceuticals

Development of Radioiodinated Tetrahydropyrazolopyridine Inhibitors Targeting mIDH.

  • Sarandeep Kaur1,2
  • Sladjana Dukic-Stefanovic1
  • Lucie Arnaud3
  • Jean-Michel Chezal3
  • Barbara Wenzel1
  • Rareş-Petru Moldovan1
  • Klaus Kopka1,2,4,5
  • Aurélie Maisonial-Besset3
5 affiliations
  1. 1Research Site Leipzig, Department of Experimental Neurooncological Radiopharmacy, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Leipzig, Germany.
  2. 2Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Germany.
  3. 3Inserm, Imagerie Moléculaire et Stratégies Théranostiques, UMR 1240, Université Clermont Auvergne, Clermont-Ferrand, France.
  4. 4German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
  5. 5National Center for Tumor Diseases (NCT), NCT/UCC Dresden, a Partnership Between DKFZ Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
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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 [¹²⁵I]SK140 and [¹²⁵I]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.

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Cite

BibTeXRIS
BibTeX
@article{kaur2026development,
  title = {{Development of Radioiodinated Tetrahydropyrazolopyridine Inhibitors Targeting mIDH.}},
  author = {Sarandeep Kaur and Sladjana Dukic-Stefanovic and Lucie Arnaud and Jean-Michel Chezal and Barbara Wenzel and Rareş-Petru Moldovan and Klaus Kopka and Aurélie Maisonial-Besset},
  journal = {Journal of labelled compounds \& radiopharmaceuticals},
  year = {2026},
  month = oct,
  doi = {10.1002/jlcr.70039},
  url = {https://europepmc.org/article/MED/42950802},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Development of Radioiodinated Tetrahydropyrazolopyridine Inhibitors Targeting mIDH.
AU  - Sarandeep Kaur
AU  - Sladjana Dukic-Stefanovic
AU  - Lucie Arnaud
AU  - Jean-Michel Chezal
AU  - Barbara Wenzel
AU  - Rareş-Petru Moldovan
AU  - Klaus Kopka
AU  - Aurélie Maisonial-Besset
PY  - 2026
DA  - 2026/10/28
JO  - Journal of labelled compounds & radiopharmaceuticals
DO  - 10.1002/jlcr.70039
UR  - https://europepmc.org/article/MED/42950802
AB  - 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 [¹²⁵I]SK140 and [¹²⁵I]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.
SN  - 0362-4803
SN  - 1099-1344
ER  -