TY  - JOUR
AU  - Kaur, Sarandeep
AU  - Dukic-Stefanovic, Sladjana
AU  - Deuther-Conrad, Winnie
AU  - Toussaint, Magali
AU  - Wenzel, Barbara
AU  - Lönnecke, Peter
AU  - Donat, Cornelius K
AU  - Moldovan, Rareş-Petru
AU  - Kopka, Klaus
TI  - From Inhibitors to PET: SAR-Based Development of [18F]SK60 for mIDH1 Imaging.
JO  - Journal of medicinal chemistry
VL  - 68
IS  - 13
SN  - 0095-9065
CY  - Washington, DC
PB  - ACS
M1  - DKFZ-2025-01331
SP  - 13750 - 13771
PY  - 2025
AB  - 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.
KW  - Structure-Activity Relationship
KW  - Positron-Emission Tomography: methods
KW  - Humans
KW  - Fluorine Radioisotopes: chemistry
KW  - Animals
KW  - Isocitrate Dehydrogenase: antagonists & inhibitors
KW  - Isocitrate Dehydrogenase: metabolism
KW  - Isocitrate Dehydrogenase: genetics
KW  - Radiopharmaceuticals: chemistry
KW  - Radiopharmaceuticals: chemical synthesis
KW  - Radiopharmaceuticals: pharmacokinetics
KW  - Brain: metabolism
KW  - Brain: diagnostic imaging
KW  - Enzyme Inhibitors: chemistry
KW  - Enzyme Inhibitors: pharmacology
KW  - Enzyme Inhibitors: chemical synthesis
KW  - Mice
KW  - Fluorine Radioisotopes (NLM Chemicals)
KW  - Isocitrate Dehydrogenase (NLM Chemicals)
KW  - Radiopharmaceuticals (NLM Chemicals)
KW  - Fluorine-18 (NLM Chemicals)
KW  - Enzyme Inhibitors (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40581853
C2  - pmc:PMC12257540
DO  - DOI:10.1021/acs.jmedchem.5c00584
UR  - https://inrepo02.dkfz.de/record/302791
ER  -