Home Blog of Signal Transduction Metabolism PDE [18F]ONO-8430506: A novel radioligand for PET imaging of autotaxin (ATX)

Category

Archives

Popular Post

ESKM, a novel therapeutic agent for sensitive and resistant PH+ leukemias

The mechanism of resistance to JAK2 inhibitor in myeloproliferative neoplasms patients

Effects of PARP inhibitors in BRCA gene-mutated ovarian cancer

DASATINIB; An inhibitor of Receptor Tyrosine Kinase

GP130/JAK/STAT3 signaling pathway induces multiple myeloma

[18F]ONO-8430506: A novel radioligand for PET imaging of autotaxin (ATX)

We have prepared and tested radioligand [18F]ONO-8430506 ([18F]8) as a novel ATX PET imaging agent derived from highly potent ATX inhibitor ONO-8430506. Radioligand [18F]8 could be prepared in good and reproducible radiochemical yields of 35 ± 5% (n = 6) using late-stage radiofluorination chemistry. ATX binding analysis showed that 9-benzyl tetrahydro-b-carboline 8 has about five times better inhibitory potency than clinical candidate GLPG1690 and somewhat less inhibitory potency than ATX inhibitor PRIMATX. The binding mode for compound 8 inside the catalytic pocket of ATX using computational modelling and docking protocols revealed that compound 8 resembled a comparable binding mode to that of ATX inhibitor GLPG1690. However, PET imaging studies with radioligand [18F]8 showed only relatively low tumour uptake and retention (SUV60min 0.21 ± 0.03) in the tested 8305C human thyroid tumour model reaching a tumour-to-muscle ratio of ∼ 2.2 after 60 min.

 

Comments:

The researchers have developed and evaluated a radioligand called [18F]ONO-8430506 ([18F]8) as a potential PET imaging agent for ATX (autotaxin). [18F]8 was derived from a highly potent ATX inhibitor called ONO-8430506. The radiochemical synthesis of [18F]8 yielded good and reproducible results, with a radiochemical yield of 35 ± 5% (n = 6) using late-stage radiofluorination chemistry.

The binding analysis of [18F]8 to ATX demonstrated that the compound, specifically the 9-benzyl tetrahydro-b-carboline 8, exhibited approximately five times better inhibitory potency compared to the clinical candidate GLPG1690. However, it showed slightly lower inhibitory potency than the ATX inhibitor PRIMATX. Computational modeling and docking protocols were used to study the binding mode of compound 8 within the catalytic pocket of ATX. The results indicated that compound 8 exhibited a binding mode similar to that of the ATX inhibitor GLPG1690.

Despite promising results from the binding analysis and computational modeling, PET imaging studies with [18F]8 showed relatively low uptake and retention in the tested 8305C human thyroid tumor model. The standardized uptake value (SUV) at 60 minutes (SUV60min) was measured at 0.21 ± 0.03, indicating low tumor uptake. The tumor-to-muscle ratio reached approximately 2.2 after 60 minutes, suggesting limited tumor-specific accumulation of the radioligand.

These findings indicate that although compound 8 demonstrated potent inhibitory activity against ATX and exhibited a binding mode similar to GLPG1690, its performance as a PET imaging agent in the tested tumor model was suboptimal. Further research and optimization may be required to improve the tumor uptake and retention of [18F]8 for effective ATX PET imaging.

Related Products

Cat.No. Product Name Information
S8895 Ziritaxestat (GLPG1690) Ziritaxestat (GLPG1690) is a selective autotaxin inhibitor with an IC50 of 131 nM and Ki of 15 nM.

Related Targets

PDE