guest ::
| Home > Publications database > From Inhibitors to PET: SAR-Based Development of [18F]SK60 for mIDH1 Imaging. |
| Home > Publications database > From Inhibitors to PET: SAR-Based Development of [18F]SK60 for mIDH1 Imaging. |
| Journal Article | DKFZ-2025-01331 |
; ; ; ; ; ; ; ;
2025
ACS
Washington, DC
Abstract: Mutations in isocitrate dehydrogenase 1/2 (mIDH1/2) are clinically significant biomarkers for diagnosis, prognosis, and therapy in cancer. To advance the noninvasive molecular imaging of mIDH1, we aim to develop a positron emission tomography (PET) radiotracer targeting IDH1R132H, the most common type of mIDH1/2. Starting from compound GSK321, a systematic structure-activity relationships (SAR) optimization was performed leading to the dimethylated derivative SK60 (19) with low nanomolar potency and high selectivity for IDH1R132H. Consequently, [18F]SK60 was developed via copper-mediated radiofluorination. Various in vitro studies with [18F]SK60 showed a high fraction of nonspecific binding. The in vivo evaluation revealed high metabolic stability with no detectable brain-permeable radiometabolite. In addition, limited brain uptake was observed by PET suggesting that further structural modifications to reduce lipophilicity might be needed for this structure. The present study led thus to a novel series of dimethylated GSK321 derivatives for further investigation in IDH1R132H-related therapies and PET imaging.
Keyword(s): Structure-Activity Relationship (MeSH) ; Positron-Emission Tomography: methods (MeSH) ; Humans (MeSH) ; Fluorine Radioisotopes: chemistry (MeSH) ; Animals (MeSH) ; Isocitrate Dehydrogenase: antagonists & inhibitors (MeSH) ; Isocitrate Dehydrogenase: metabolism (MeSH) ; Isocitrate Dehydrogenase: genetics (MeSH) ; Radiopharmaceuticals: chemistry (MeSH) ; Radiopharmaceuticals: chemical synthesis (MeSH) ; Radiopharmaceuticals: pharmacokinetics (MeSH) ; Brain: metabolism (MeSH) ; Brain: diagnostic imaging (MeSH) ; Enzyme Inhibitors: chemistry (MeSH) ; Enzyme Inhibitors: pharmacology (MeSH) ; Enzyme Inhibitors: chemical synthesis (MeSH) ; Mice (MeSH) ; Fluorine Radioisotopes ; Isocitrate Dehydrogenase ; Radiopharmaceuticals ; Fluorine-18 ; Enzyme Inhibitors
; BIOSIS Previews ; Biological Abstracts ; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; Index Chemicus ; Nationallizenz
; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection
|
The record appears in these collections: |
