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  • We performed three baseline scans in two


    We performed three baseline scans in two baboons and one blocking study by administering 1 mg/kg (i.v) meloxicam 30 min prior to [C]TMI injection (injected activity 175.75 ± 18.5 MBq, mass of unlabeled TMI < 2 μg) under anesthetic conditions. Baseline PET studies show that [C]TMI penetrates the blood nibr barrier (BBB) and retained in brain with a somewhat heterogeneous pattern (). Time activity curves (TACs) expressed in standard uptake value (SUV) indicated a peak uptake of the radiotracer at an interval between 3 and 9 min post-injection in various brain regions, followed by a gradual washout of activity (). The highest and lowest uptake of [C]TMI was found in thalamus and orbital cortex, respectively (). [C]TMI exhibited low uptake in brain in the post-drug PET scan (). TACs of meloxicam-treated baboon indicated partial blocking and the SUV values were 20–30% lower compared to baseline across the brain regions (). The radioactivity levels in baboon plasma peaked around one min post injection, followed by a gradual clearance (, n = 4). High-performance liquid chromatography (HPLC) analyses of the plasma samples indicated no significant metabolism of [C]TMI in the baseline scans (, n = 3). However, a relatively faster metabolism is found with meloxicam block scan: [C]TMI parent fraction in this case was 88.5% at 2 min, 81.6% at 4 min, 79.4% at 12 min, 75.8% at 30 min, 79.2% at 60 min, and 78% at 90 min post injection, respectively (, n = 1). Metabolite-corrected arterial input functions were used to estimate [C]TMI total volume of distribution (V) values using a one-tissue compartment (1-TC), Logan plot and likelihood estimation in graphical analysis (LEGA)., , All tested quantification approaches provided comparable V values in the range of 3.2–7 (mL/cm) (). The coefficients of variations of baseline V values were 5.4% (I-TC), 8.6% (Logan) and 9.8% (LEGA) respectively (n = 3). The percentage difference between [C]TMI V values measured at baseline and after blocking is about 26% (). Frontal cortex and thalamus exhibit highest V changes (35% and 28%), followed by cingulate cortex, cerebellum (24% each) and hippocampus (20%) with respect to baseline and blocking scans. Orbital cortex exhibits lowest V changes (11%) of [C]TMI. We also noticed ∼20% faster metabolism of [C]TMI in meloxicam blocking experiment (n = 1). Further studies are required to verify the effect of meloxicam on [C]TMI metabolism. The above results indicate that [C]TMI exhibits good washout characteristics for binding parameter measurements and moderate specific binding in normal brain. Determination of the level of [C]TMI specific binding with COX-2 in animal models of inflammation or diseases with higher expression of COX-2, can further establish the use of [C]TMI for brain imaging with PET. Acknowledgements Pfizer Inc., USA provided funding for this investigator initiated grant request (JSDK and JJM). We thank NIMH-PDSP for competitive binding assay of TMI.
    Introduction Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most prevalent pharmaceuticals in the world [1]. Because they are potent inhibitors of cyclooxygenase (COX) enzymes, they reduce the synthesis of pro-inflammatory prostaglandins (PGs) [2]. They are employed for their analgesic, antipyretic, and anti-inflammatory properties. Two related isozymes of the COX have been described, constitutive COX-1 and inducible COX-2 [3], [4]. These two isoforms are genetically independent proteins located on different chromosomes. The binding sites are almost identical and the two COX isoforms share high sequence homology of 65%. nibr COX-2 is an inducible isozyme implicated in different pathological processes such as several cancer types and inflammation. There are three main differences in the amino acids sequence between the COX-1 and COX-2 active sites. These structural differences produce main implications for the selectivity profile of NSAIDs [5]. For example, the substitution of valine 523 in the active site of the COX-2 for a relatively bulky isoleucine residue in COX-1 creates an additional side pocket. An access to this extra binding pocket is limited in the case of binding to COX-1 [6], [7], [8]. Prolonged administration of non-selective NSAIDs exhibit several undesired adverse drug reactions (ADRs) like gastrointestinal irritation, bleeding and ulceration. The main cause of such ADRs is the inhibitory effect on the gastroprotective prostanoids produced by COX-1 enzymes in the gastrointestinal tract [9], [10], [11], [12], [13], [14]. Therefore, introduction of potent and selective COX-2 inhibitors with more favorable gastro-intestinal safety profile has become of great interest [15]. Moreover, the use of non-acidic prodrugs could decrease the direct ulcerogenic properties of acidic agents and improve the selectivity profile of NSAIDs toward COX-2 isoenzyme [16], [17].