In Vivo Brain Imaging, Biodistribution, and Radiation Dosimetry Estimation of [11C]Celecoxib, a COX-2 PET Ligand, in Nonhuman Primates.

J Kumar,Francesca Zanderigo,Jaya Prabhakaran,Christine Delorenzo,Ramin Parsey,Bing Bai,J Mann

doi:10.3390/molecules23081929

Abstract

COX-2 selective inhibitors (COXIBs) are non-steroidal anti-inflammatory drugs (NSAIDs), with fewer side effects compared with non-selective NSAIDs, and are used for the treatment of arthritis, headaches, and other inflammatory diseases of the brain and peripheral tissues. Radiolabeled COXIBs may permit positron emission tomography (PET) imaging of COX-2 localization and activity in diseases, enable monitoring of inflammatory processes, and determine target occupancy of COX-2 activity by NSAIDs, thus, accelerating the development of novel CIXIBs. We synthesized [11C]celecoxib, one of the COXIBs and a prescription drug, and here report its in vivo uptake in the brain, whole body biodistribution, and radiation dosimetry in baboons using PET. Brain imaging experiments were performed in one baboon and whole body PET scans were performed in triplicates in two male baboons using an ECAT ACCEL (Siemens Medical Solutions, Inc. Knoxville) under anesthetic conditions. PET studies in baboons show that [11C]celecoxib penetrates the blood brain barrier (BBB) and accumulates in the brain, followed by a washout of radioactivity. The liver has the highest residence time and the gallbladder is the critical organ for [11C]celecoxib. Organ Level Internal Dose Assessment (OLINDA) estimates indicate that the maximum permissible single study dosage of [11C]celecoxib in humans is 1110 MBq (30 mCi) for both males and females under the 21 CFR 361.1 dose limit for research subjects.

Highlights

Cyclooxygenase (COX) is an enzyme involved in the biosynthesis of prostaglandins, prostanoids, and thromboxins from arachidonic acid and drugs that block COX-1 and COX-2 isoenzymes that are non-steroidal anti-inflammatory drugs (NSAIDs) [1,2,3]
C]celecoxib in the baboon brain normalized by injected radioactive dose and body weight
Whole body biodistribution and dosimetry estimations of [11 C]celecoxib in baboons were performed based on a protocol we developed earlier [28,29,30,31,32]

Summary

Introduction

Cyclooxygenase (COX) is an enzyme involved in the biosynthesis of prostaglandins, prostanoids, and thromboxins from arachidonic acid and drugs that block COX-1 and COX-2 isoenzymes that are non-steroidal anti-inflammatory drugs (NSAIDs) [1,2,3]. Of these two isoenzymes of COX, COX-1, is constitutively expressed in many tissues and is responsible for the production of prostanoids associated with normal haemostatic functions [4]. Expression of COX-2 proteins and mRNA in COX-2 levels in normal tissues arelevels the highest in thetissues kidney followed by brain, the spleen, liver, human subjects show that.

Radiochemistry

Decay-corrected

Whole Body

Experimental

Conclusions