Cyclooxygenase-2 (COX-2) is induced during inflammatory stimuli and its inhibition underlies the therapeutic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs). Neuroinflammation plays a significant role in the pathogenesis of neurodegenerative diseases such as Alzheimer?s disease (AD), Parkinson?s disease (PD), amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), and stroke. COX-2 induction is also associated with inflammatory arthritis, acute organ rejection, cancers, and pain. Non-invasive quantification of COX-2 expression throughout the course of disease may be crucial to determine the exact time window for maximum COX-2 induction and assess whether therapy involving COX-2 inhibition is an effective treatment strategy. A positron emission tomography (PET) ligand to quantify alterations of COX-2 in brain diseases is not identified yet, due to the scarcity of qualified COX-2 inhibitors. In order to establish a clinically beneficial PET ligand for quantifying COX-2 in brain, we propose to evaluate highly potent 18F-labeled COX-2 inhibitors due to the advantages associated with the 110-minute half-life. 18F-tracers would enable equilibrium scanning to allow robust kinetic studies and accurate quantification of COX-2, thereby providing a biomarker for in vivo disease staging as well as treatment evaluation. Moreover, 18F-tracers can be transported to nearby centers without a cyclotron and facilitate cost-effective PET studies. Hence, we identified a high affinity COX-2 inhibitor (IC50 = 2.2 nM), MTP (Figure 2), possessing an aromatic 18F-labeling site that is less susceptible for defluorination. MTP also has adequate lipophilicity (LogP=2.7) to passively traverse the blood-brain barrier (BBB). We synthesized [18F]MTP and successfully demonstrated its specific binding in COX-2 positive BxPC-3 cell lines (Figure 3) via blocking studies. Also, PET imaging in mice, intracranially administered with lipopolysaccharide (LPS), showed a significantly higher binding of [18F]MTP in brain compared to binding in vehicle treated controls, with no visible skeletal uptake (Figure 4). Subsequent in vitro autoradiography of slide-mounted sections of the harvested brain, established the specific binding of [18F]MTP to COX-2 in LPS-induced mice with neuroinflammation (Figures 5 & 6). In light of the above supporting evidence, [18F]MTP will be further evaluated as a lead tracer, along with two backup ligands 2 & 3 (Figure 2), using additional PET imaging in mice models of neuroinflammation as well as amyloid neuropathology (Aims 1 & 2). The most qualified tracer identified from mice PET imaging studies will undergo test-retest dynamic PET evaluations with concomitant arterial blood sampling in male and female anesthetized monkeys to quantify binding as total distribution volume in various brain regions via kinetic modeling (Aim 3). We believe, the proposed experiments would lead to the identification of a new 18F-COX-2 PET tracer, characterized for facile transition to clinical studies and potentially assist early diagnosis, monitoring therapeutic response, and aid development of new NSAID medications by dose response studies using PET imaging.

Public Health Relevance

Cyclooxygenase-2 (COX-2) plays a crucial role in the inflammatory pathogenesis of neurological disorders, cancers, arthritis, organ rejection as well as pain. Positron emission tomography (PET) imaging using radiolabeled COX-2 inhibitors would be a useful tool for noninvasive quantification of COX-2 in diseases and thereby allow accurate diagnosis, disease staging, therapy evaluation, and development of new anti- inflammatory medications. The goal of this proposal is to develop such a PET ligand, clinically useful for COX- 2 imaging in neurological diseases.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Drug Discovery for the Nervous System Study Section (DDNS)
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Hsiao, John
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New York State Psychiatric Institute
New York
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