Abstract
Neuroinflammation and cyclooxygenase-2 (COX-2) upregulation are associated with the pathogenesis of degenerative brain diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), epilepsy, and a response to traumatic brain injury (TBI) or stroke. COX-2 is also induced in acute pain, depression, schizophrenia, various cancers, arthritis and in acute allograft rejection. Positron emission tomography (PET) imaging allows for the direct measurement of in vivo COX-2 upregulation and thereby enables disease staging, therapy evaluation and aid quantifying target occupancy of novel nonsteroidal anti-inflammatory drugs or NSAIDs. Thus far, no clinically useful radioligand is established for monitoring COX-2 induction in brain diseases due to the delay in identifying qualified COX-2-selective inhibitors entering the brain. This review examines radiolabeled COX-2 inhibitors reported in the past decade and identifies the most promising radioligands for development as clinically useful PET radioligands. Among the radioligands reported so far, the three tracers that show potential for clinical translation are, [11CTMI], [11C]MC1 and [18F]MTP. These radioligands demonstrated BBB permeablity and in vivo binding to constitutive COX-2 in the brain or induced COX-2 during neuroinflammation.
Highlights
Role of COX-2 in the Central Nervous System (CNS). Both COX-1 and COX-2 are expressed in the CNS and are associated with neuroinflammation, COX-2 is the predominant isoform found in the brain and spinal cord [17]
A high affinity and selective COX-2 radioligand would detect the upregulation of COX-2 in LPS models, and that can be confirmed by blocking studies using Positron emission tomography (PET) imaging
COX-2 is an important target for the PET imaging of neuroinflammation in neurodegenerative diseases
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. While the functional sites are conserved, conformational variations due to a few crucial substitutions in the 434 and 523 positions of the active site pockets contribute to their different affinities for specific inhibitors [7] Both COX-1 and COX-2 are inhibited by NSAIDs, which have been used in the treatment of inflammation and pain for more than a century (e.g., aspirin and ibuprofen) [8,9]. High affinity and selective coxibs can serve as imaging agents to study the underlying mechanism of inflammatory diseases associated with COX-2 induction and are promising aids in the development of novel safe and effective coxibs Both COX-1 and COX-2 are expressed in the CNS and are associated with neuroinflammation, COX-2 is the predominant isoform found in the brain and spinal cord [17]. Due to the significance of COX-2 in behavioral and cognitive functions and as a treatment target for brain diseases, measuring COX-2 levels in the brain is essential for medication selection and the monitoring of the treatment effect
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