Journal Article

DKFZ-2026-02688

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Development of Radioiodinated Tetrahydropyrazolopyridine Inhibitors Targeting mIDH.

Kaur, S. ; Dukic-Stefanovic, S. ; Arnaud, L. ; Chezal, J.-M. ; Wenzel, B. ; Moldovan, R.-P. ; Kopka, K.DKFZ* ; Maisonial-Besset, A.

2026
Wiley New York, NY [u.a.]

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.

Keyword(s): Pyridines: chemistry (MeSH) ; Pyridines: pharmacology (MeSH) ; Pyridines: chemical synthesis (MeSH) ; Pyrazoles: chemistry (MeSH) ; Pyrazoles: pharmacology (MeSH) ; Pyrazoles: chemical synthesis (MeSH) ; Iodine Radioisotopes: chemistry (MeSH) ; Halogenation (MeSH) ; Enzyme Inhibitors: pharmacology (MeSH) ; Enzyme Inhibitors: chemistry (MeSH) ; Enzyme Inhibitors: chemical synthesis (MeSH) ; Humans (MeSH) ; Pyridines ; Pyrazoles ; Iodine Radioisotopes ; Enzyme Inhibitors

Note: #DKTKZFB26# / #NCTZFB26#

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Dresden (DD01)
2. Koordinierungsstelle NCT Dresden (DD04)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF < 5 ; Index Chemicus ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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