Abstract
Non-invasive imaging of cyclooxygenase-2 (COX-2) by radiolabeled ligands is attractive for the diagnosis of cancer, and novel highly affine leads with optimized pharmacokinetic profile are of great interest for future developments. Recent findings have shown that methylsulfonyl-substituted (dihydro)pyrrolo[3,2,1-hi]indoles represent highly potent and selective COX-2 inhibitors but possess unsuitable pharmacokinetic properties for radiotracer applications. Based on these results, we herein present the development and evaluation of a second series of sulfonamide-substituted (dihydro)pyrrolo[3,2,1-hi]indoles and their conversion into the respective more hydrophilic N-propionamide-substituted analogs. In comparison to the methylsulfonyl-substituted leads, COX inhibition potency and selectivity was retained in the sulfonamide-substituted compounds; however, the high lipophilicity might hinder their future use. The N-propionamide-substituted analogs showed a significantly decreased lipophilicity and, as expected, lower or no COX-inhibition potency. Hence, the N-(sulfonyl)propionamides can be regarded as potential prodrugs, which represents a potential approach for more sophisticated radiotracer developments.
Highlights
Cyclooxygenases (COX) convert arachidonic acid into prostaglandin H2, which is the rate limiting step in the synthesis of prostanoids
Fast excretion from the body, and high lipophilicity, which is in principal needed to address the lipophilic binding site in COX-2—and in turn leads to high binding in off-target tissues like white adipose tissue—can be considered as main reasons for the inability of previously synthesized imaging agents to visualize
A potent and selective COX-2 inhibitor having a 1,2-dihydropyrrolo[3,2,1-hi]indole core and a methylsulfonyl group was labeled with fluorine-18 by us and evaluated in vitro and in vivo
Summary
Cyclooxygenases (COX) convert arachidonic acid into prostaglandin H2 , which is the rate limiting step in the synthesis of prostanoids. These are potent lipid mediators that control a variety of physiological and pathophysiological processes. While COX-1 is mainly responsible for the production of prostanoids to maintain homeostatic processes, e.g., in the gastric mucosa, COX-2 represents a key player in inflammation. It is nearly absent in most tissues under physiological conditions, but its expression is induced by inflammatory and proliferative stimuli to provide. Non-invasive imaging of COX-2 in vivo by means of radiolabeled probes for single photon emission computed tomography (SPECT) or positron emission tomography
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