In vivo evaluation of [11C]TMI, a COX-2 selective PET tracer, in baboons.

Abstract

Overexpression of Cyclooxygenase-2 (COX-2) enzyme is associated with the pathogenesis of inflammation, cancers, stroke, arthritis, and neurological disorders. Because of the involvement of COX-2 in these diseases, quantification of COX-2 expression using Positron Emission Tomography (PET) may be a biological marker for early diagnosis, monitoring of disease progression, and an indicator of effective treatment. At present there is no target-specific or validated PET tracer available for in vivo quantification of COX-2. The objective of this study is to evaluate [11C]TMI, a selective COX-2 inhibitor (Ki ≤ 1 nM) in nonhuman primates using PET imaging. PET imaging in baboons showed that [11C]TMI penetrates the blood brain barrier (BBB) and accumulates in brain in a somewhat heterogeneous pattern. Metabolite analyses indicated that [11C]TMI undergoes no significant metabolism of parent tracer in the plasma for baseline scans, however a relative faster metabolism was found for blocking scan. All the tested quantification approaches provide comparable tracer total distribution volume (VT) estimates in the range of 3.2-7 (mL/cm3). We observed about 25% lower VT values in blocking studies with meloxicam, a nonselective COX-2 inhibitor, compared to baseline [11C]TMI binding. Our findings indicate that [11C]TMI may be a suitable PET tracer for the quantification of COX-2 in vivo. Further experiments are needed to confirm the potential of this tracer in COX-2 overexpressing models for brain diseases.

• Authors: J S Dileep Kumar, Francesca Zanderigo, Jaya Prabhakaran, Harry Rubin-Falcone, Ramin V Parsey, J John Mann
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 28 Issue 23-24 Pg. 3592-3595 (12 15 2018) ISSN: 1464-3405 [Electronic] England
• PMID: 30396759 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018. Published by Elsevier Ltd.

Chemical References

• 3-(4-methylsulfonylphenyl)-4-phenyl-5-trifluoromethylisoxazole
• Carbon Radioisotopes
• Carbon-11
• Cyclooxygenase 2 Inhibitors
• Isoxazoles
• Radiopharmaceuticals
• Sulfones
• Cyclooxygenase 2

Topics

• Animals
• Blood-Brain Barrier (metabolism)
• Brain (diagnostic imaging, metabolism)
• Carbon Radioisotopes (chemistry)
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase 2 Inhibitors (blood, chemistry, metabolism)
• Isoxazoles (blood, chemistry, metabolism)
• Papio
• Positron-Emission Tomography
• Radiopharmaceuticals (blood, chemistry, metabolism)
• Sulfones (blood, chemistry, metabolism)