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From Inhibitors to PET: SAR-Based Development of [18F]SK60 for mIDH1 Imaging.
Sarandeep Kaur1,2, Sladjana Dukic-Stefanovic1, Winnie Deuther-Conrad1
1Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Department of Experimental Neurooncological Radiopharmacy, Research Site Leipzig, Leipzig 04318, Germany.
Journal of Medicinal Chemistry
|June 29, 2025
Summary
Researchers developed [18F]SK60, a novel PET radiotracer targeting IDH1R132H mutations in cancer. While showing good stability, further optimization is needed to improve brain uptake for effective molecular imaging.
Area of Science:
- Oncology
- Molecular Imaging
- Radiochemistry
Background:
- Mutations in isocitrate dehydrogenase 1/2 (mIDH1/2) are crucial biomarkers in cancer diagnosis, prognosis, and treatment.
- Noninvasive molecular imaging of mIDH1 is essential for advancing cancer diagnostics and therapeutics.
Purpose of the Study:
- To develop a novel positron emission tomography (PET) radiotracer targeting the IDH1R132H mutation, the most common mIDH1/2 variant.
- To optimize a lead compound (GSK321) for enhanced potency and selectivity against IDH1R132H.
Main Methods:
- Systematic structure-activity relationship (SAR) optimization of GSK321 led to the potent derivative SK60.
- [18F]SK60 was synthesized using copper-mediated radiofluorination.
- In vitro and in vivo studies were conducted to evaluate the radiotracer's binding, metabolic stability, and brain uptake.
Main Results:
- SK60 demonstrated low nanomolar potency and high selectivity for IDH1R132H.
- [18F]SK60 exhibited high metabolic stability in vivo with no detectable brain-permeable radiometabolites.
- Limited brain uptake was observed, indicating a need for lipophilicity reduction in future iterations.
Conclusions:
- A novel series of dimethylated GSK321 derivatives, including [18F]SK60, were developed for potential IDH1R132H-targeted PET imaging.
- Further structural modifications are necessary to enhance brain penetration for improved PET imaging applications.
- These findings support the ongoing development of targeted imaging agents for IDH1R132H-mutated cancers.
