PET measurement of cyclooxygenase-2 using a novel radioligand: upregulation in primate neuroinflammation and first-in-human study.

Background: Cyclooxygenase-2 (COX-2), which is rapidly upregulated by inflammation, is a key enzyme catalyzing the rate-limiting step in the synthesis of several inflammatory prostanoids. Successful positron emission tomography (PET) radioligand imaging of COX-2 in vivo could be a potentially powerful tool for assessing inflammatory response in the brain and periphery. To date, however, the development of PET radioligands for COX-2 has had limited success.

2-(4-Methylsulfonylphenyl)pyrimidines as Prospective Radioligands for Imaging Cyclooxygenase-2 with PET-Synthesis, Triage, and Radiolabeling.

Cyclooxygenase 2 (COX-2) is an inducible enzyme responsible for the conversion of arachidonic acid into the prostaglandins, PGG2 and PGH2. Expression of this enzyme increases in inflammation. Therefore, the development of probes for imaging COX-2 with positron emission tomography (PET) has gained interest because they could be useful for the study of inflammation in vivo, and for aiding anti-inflammatory drug development targeting COX-2.

3-Substituted 1,5-Diaryl-1 H-1,2,4-triazoles as Prospective PET Radioligands for Imaging Brain COX-1 in Monkey. Part 2: Selection and Evaluation of [C]PS13 for Quantitative Imaging.

In our preceding paper (Part 1), we identified three 1,5-bis-diaryl-1,2,4-triazole-based compounds that merited evaluation as potential positron emission tomography (PET) radioligands for selectively imaging cyclooxygenase-1 (COX-1) in monkey and human brain, namely, 1,5-bis(4-methoxyphenyl)-3-(alkoxy)-1 H-1,2,4-triazoles bearing a 3-methoxy (PS1), a 3-(2,2,2-trifluoroethoxy) (PS13), or a 3-fluoromethoxy substituent (PS2). PS1 and PS13 were labeled from phenol precursors by O-C-methylation with [C]iodomethane and PS2 by O-F-fluoroalkylation with [H,F]fluorobromomethane. Here, we evaluated these PET radioligands in monkey.

3-Substituted 1,5-Diaryl-1 H-1,2,4-triazoles as Prospective PET Radioligands for Imaging Brain COX-1 in Monkey. Part 1: Synthesis and Pharmacology.

Cyclooxygenase-1 (COX-1) is a key enzyme in the biosynthesis of proinflammatory thromboxanes and prostaglandins and is found in glial and neuronal cells within brain. COX-1 expression is implicated in numerous neuroinflammatory states. We aim to find a direct-acting positron emission tomography (PET) radioligand for imaging COX-1 in human brain as a potential biomarker of neuroinflammation and for serving as a tool in drug development.

In vitro evaluation of guanidine analogs as sigma receptor ligands for potential anti-stroke therapeutics.

Currently, the only Food and Drug Administration-approved treatment of acute stroke is recombinant tissue plasminogen activator, which must be administered within 6 hours after stroke onset. The pan-selective σ-receptor agonist N,N'-di-o-tolyl-guanidine (o-DTG) has been shown to reduce infarct volume in rats after middle cerebral artery occlusion, even when administered 24 hours after stroke. DTG derivatives were synthesized to develop novel compounds with greater potency than o-DTG.

Ligand-free copper-catalyzed arylation of amidines.

Copper-catalyzed cross-coupling reactions of amidine salts were utilized to synthesize monoarylated amidines in moderate to high yields with ligand-free conditions. DMF was the superior solvent for the N-arylation of benzamidines, while MeCN was used in the formation of N-aryl amidines in moderate to high yield.

Copper-catalyzed guanidinylation of aryl iodides: the formation of N,N'-disubstituted guanidines.

A copper-catalyzed cross-coupling reaction of guanidine nitrate with aryl iodides was used for the formation of N,N'-disubstituted guanidines to be used as potential therapeutics for strokes. A relatively inexpensive commercially available guanidine salt and a series of aryl iodides together with copper iodide and N,N-diethylsalicylamide as an efficient catalyst/ligand system provided a simple diarylation procedure.