11C-Labeled Analogs of Indomethacin Esters and Amides for Brain Cyclooxygenase-2 Imaging: Radiosynthesis, in Vitro Evaluation and in Vivo Characteristics in Mice

Abstract

Cyclooxygenase (COX) is the crucial enzyme in the conversion of arachidonic acid to prostaglandins. It exists at least in two isoforms, a constitutive form (COX-1) and an inducible form (COX-2), 1-3) although a third distinct COX isozyme has also been reported.4) The COX-1 enzyme is responsible for maintaining homeostasis whereas COX-2 is induced during inflammation by various stimuli and, in some tissues including the brain, kidney and placenta, is also constitutively expressed. Recent studies indicate that elevated expression of COX-2 has been implicated in many pathological events, including rheumatoid arthritis, cancer, heart disease, and neurodegenerative disorders. 5)In the brain, COX-2 is mainly expressed in the cortex, hypothalamus, and hippocampus, 6) and is upregulated in neurological disorders such as Parkinson's disease and Alzheimer's disease, [7][8][9] although the functions of COX-2 in pathophysiological processes are not yet well-understood. There is great potential that COX-2-targeted imaging by positron emission tomography (PET) may provide useful information on the role of this enzyme, especially in various neurological disorders, and also may help to evaluate the efficacy of selective COX-2 inhibitors. 10) Thus, many COX-2 inhibitors have been labeled with a suitable radionuclide for mapping the enzymes in vivo. However, previously evaluated PET radiotracers, including 11 C-labeled COX inhibitors of the diarylheterocyclic class which were synthesized by us, 11,12) have only achieved limited success, due to a lack of sufficient specific-binding to the COX-2 enzyme and/or sufficient brain penetration, in spite of promising in vitro pharmacological data. [13][14][15][16][17][18] There is a need for systematic studies correlating the physicochemical properties of agents with their in vivo behavior for a better design of COX-2 imaging probes.Currently, many selective COX-2 inhibitors with various structural features, as exemplified by vicinal diaryl heterocycles such as celecoxib and refecoxib, have been developed as non-steroidal anti-inflammatory drugs (NSAIDs) with improved gastric safety profiles.19) Most of them have high lipophilicity. Indomethacin is a traditional non-selective inhibitor of the COX isozyme which is widely used as a NSAID, but with poor brain penetration largely due to the presence of the carboxylic acid moiety. 20) Interestingly, recent studies concerning ester and amide derivatives of indomethacin have found very high COX-2 inhibition potency and a high degree of COX-2-selectivity.21-23) Marnett and colleagues synthesized 123 I-labeled N-iodobenzyl-containing amide derivative of indomethacin as a COX-2 imaging agent, which exhibited sufficient stability in COX-2 expressing nude mouse tumor.24) More recently, using organic fluorophores tethered to indomethacin through an amide linkage, the feasibility of specific in vivo targeting of COX-2 in inflammatory lesions in mice has been demonstrated by the same group. 25)The purpose of this study is to find suitable radioligands ...

Development of a 18F‐labeled Diaryl‐Substituted Dihydropyrrolo[3,2,1‐hi]indole as Potential Probe for Functional Imaging of Cyclooxygenase‐2 with PET

“…Results obtained by small animal PET imaging were consistent with that of biodistribution experiments demonstrating a rapid clearance of [ 18 F] DHPI from the blood and a fast accumulation of radioactivity in liver and intestine (Figure A). This is consistent with high nonspecific binding of [ 18 F] DHPI and has also been observed for other radiolabeled coxibs with high lipophilicity, like indole [ 18 F] IND , 11 C‐labeled cyclopentene, indomethacin derivatives, 18 F‐labeled azulene, and celecoxib derivatives.…”

Radiolabeled COX-2 Inhibitors for Non-Invasive Visualization of COX-2 Expression and Activity — A Critical Update

“…By using radiolabeled COX-2 inhibitors with both, high affinity and selectivity, it would be possible to obtain non-invasive and repeatable in vivo data of the functional COX-2 expression level in manifold diseases over the time that means during their manifestation, progression, and under targeted therapy. This is much more important since the involvement of COX-2 in a number of diseases is still not fully understood and, hence, non-invasive imaging would help to get a more detailed insight into the involvement of COX-2 in these pathophysiological situations [27,28,29,31,32,33,34,35,36,37,38,39]. The pharmacological data achievable from the radiotracers could help to understand the physiological behavior and metabolic pathways of the compounds itself [30,40,41].…”

Synthesis and Anti-inflammatory Activity of Some Benzofuran and Benzopyran-4-one Derivatives

“…[4][5][6] The rise of selective cyclooxygenase-2 (COX-2) inhibitors reduced the risk of some of these side effects. 7,8) Therefore, seeking new drugs with anti-inflammatory activity and a fewer side effects are still a goal for medicinal chemists.…”