Next Article in Journal
The Impact of Radiation-Induced DNA Damage on cGAS-STING-Mediated Immune Responses to Cancer
Next Article in Special Issue
PET Molecular Imaging: A Holistic Review of Current Practice and Emerging Perspectives for Diagnosis, Therapeutic Evaluation and Prognosis in Clinical Oncology
Previous Article in Journal
Administration of Human MSC-Derived Extracellular Vesicles for the Treatment of Primary Sclerosing Cholangitis: Preclinical Data in MDR2 Knockout Mice
Previous Article in Special Issue
MGMT Promoter Methylation and IDH1 Mutations Do Not Affect [18F]FDOPA Uptake in Primary Brain Tumors
Article

Radiolabeled 6-(2, 3-Dichlorophenyl)-N4-methylpyrimidine-2, 4-diamine (TH287): A Potential Radiotracer for Measuring and Imaging MTH1

1
Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA
2
Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA
3
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(22), 8860; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228860
Received: 7 October 2020 / Revised: 3 November 2020 / Accepted: 20 November 2020 / Published: 23 November 2020
MTH1 (MutT homolog 1) or NUDT1 (Nudix Hydrolase 1), also known as oxidized purine nucleoside triphosphatase, has potential as a biomarker for monitoring cancer progression and quantifying target engagement for relevant therapies. In this study, we validate one MTH1 inhibitor TH287 as a PET MTH1 radiotracer. TH287 was radiolabeled with tritium and the binding of [3H]TH287 to MTH1 was evaluated in live glioblastoma cells (U251MG) through saturation and competitive binding assays, together with in vitro enzymatic assays. Furthermore, TH287 was radiolabeled with carbon-11 for in vivo microPET studies. Saturation binding assays show that [3H]TH287 has a dissociation constant (Kd) of 1.97 ± 0.18 nM, Bmax of 2676 ± 122 fmol/mg protein for U251MG cells, and nH of 0.98 ± 0.02. Competitive binding assays show that TH287 (Ki: 3.04 ± 0.14 nM) has a higher affinity for MTH1 in U251MG cells compared to another well studied MTH1 inhibitor: (S)-crizotinib (Ki: 153.90 ± 20.48 nM). In vitro enzymatic assays show that TH287 has an IC50 of 2.2 nM in inhibiting MTH1 hydrolase activity and a Ki of 1.3 nM from kinetics assays, these results are consistent with our radioligand binding assays. Furthermore, MicroPET imaging shows that [11C]TH287 gets into the brain with rapid clearance from the brain, kidney, and heart. The results presented here indicate that radiolabeled TH287 has favorable properties to be a useful tool for measuring MTH1 in vitro and for further evaluation for in vivo PET imaging MTH1 of brain tumors and other central nervous system disorders. View Full-Text
Keywords: MTH1; radiotracer; TH287; binding assay; PET MTH1; radiotracer; TH287; binding assay; PET
Show Figures

Figure 1

MDPI and ACS Style

Chen, H.; Afrin, S.; Guo, Y.; Chu, W.; Benzinger, T.L.S.; Rogers, B.E.; Garbow, J.R.; Perlmutter, J.S.; Zhou, D.; Xu, J. Radiolabeled 6-(2, 3-Dichlorophenyl)-N4-methylpyrimidine-2, 4-diamine (TH287): A Potential Radiotracer for Measuring and Imaging MTH1. Int. J. Mol. Sci. 2020, 21, 8860. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228860

AMA Style

Chen H, Afrin S, Guo Y, Chu W, Benzinger TLS, Rogers BE, Garbow JR, Perlmutter JS, Zhou D, Xu J. Radiolabeled 6-(2, 3-Dichlorophenyl)-N4-methylpyrimidine-2, 4-diamine (TH287): A Potential Radiotracer for Measuring and Imaging MTH1. International Journal of Molecular Sciences. 2020; 21(22):8860. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228860

Chicago/Turabian Style

Chen, Huaping, Sadia Afrin, Yingqiu Guo, Wenhua Chu, Tammie L.S. Benzinger, Buck E. Rogers, Joel R. Garbow, Joel S. Perlmutter, Dong Zhou, and Jinbin Xu. 2020. "Radiolabeled 6-(2, 3-Dichlorophenyl)-N4-methylpyrimidine-2, 4-diamine (TH287): A Potential Radiotracer for Measuring and Imaging MTH1" International Journal of Molecular Sciences 21, no. 22: 8860. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228860

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop