Abstract
Multidrug resistance-associated protein 1 (MRP1) is a drug efflux transporter that has been implicated in the pathology of several neurological diseases and is associated with development of multidrug resistance. To enable measurement of MRP1 function in the living brain, a series of 6-halopurines decorated with fluorinated side chains have been synthesized and evaluated as putative pro-drug tracers. The tracers were designed to undergo conjugation with glutathione within the brain and hence form the corresponding MRP1 substrate tracers in situ. 6-Bromo-7-(2-[18F]fluoroethyl)purine showed good brain uptake and rapid metabolic conversion. Dynamic PET imaging demonstrated a marked difference in brain clearance rates between wild-type and mrp1 knockout mice, suggesting that the tracer can allow noninvasive assessment of MRP1 activity in vivo.
Highlights
Multidrug resistance-associated protein 1 (MRP1), which is encoded by the ABCC1 gene, is ubiquitously expressed in the body but is found at elevated levels in the lungs, testis, kidneys, heart, and placenta, as well as at physiological barriers including the blood−brain barrier (BBB) and the blood−cerebrospinal fluid barrier.7−10 In contrast to P-gp, it is localized on the basolateral membranes in polarized cells
We explored two alternative strategies for preparation of fluorine-18 labeled 6-halopurines, namely, direct labeling of derivatives bearing fluoroalkyl chains or indirect labeling via click chemistry to give the resulting radiolabeled triazoles
Following measurements of the conjugation rates with GSH, selected derivatives were labeled with fluorine-18, and subjected to biodistribution and metabolite studies. 6-Halopurines decorated with fluoroalkyl side chains showed high initial brain uptake, whereas introduction of triazole containing side chains proved detrimental for BBB penetration
Summary
Drug efflux transporters of the ATP-binding cassette (ABC) family of proteins mediate active transport of molecules across cell membranes and physiological barriers, and they have a major impact on the pharmacological behavior of most of the drugs in use today. ABC transporters have complementary substrate scope and expression patterns, and they maintain chemical homeostasis by extruding toxins and xenobiotics, including drugs, from cells and tissues.− In particular, multidrug resistance-associated proteins (MRPs), P-glycoprotein (P-gp), and breast cancer-related protein (BCRP) are believed to play a key role in the development of multidrug resistance by extruding an array of therapeutic drugs, resulting in reduced access to their target sites, and rendering them ineffective.MRP1, which is encoded by the ABCC1 gene, is ubiquitously expressed in the body but is found at elevated levels in the lungs, testis, kidneys, heart, and placenta, as well as at physiological barriers including the blood−brain barrier (BBB) and the blood−cerebrospinal fluid barrier.− In contrast to P-gp, it is localized on the basolateral membranes in polarized cells. ABC transporters have complementary substrate scope and expression patterns, and they maintain chemical homeostasis by extruding toxins and xenobiotics, including drugs, from cells and tissues.− In particular, multidrug resistance-associated proteins (MRPs), P-glycoprotein (P-gp), and breast cancer-related protein (BCRP) are believed to play a key role in the development of multidrug resistance by extruding an array of therapeutic drugs, resulting in reduced access to their target sites, and rendering them ineffective. MRP1 functions mainly as a cotransporter of amphipathic organic anions It can transport a variety of drugs, endogenous metabolites, xenobiotics, and hydrophobic drugs or other compounds that are conjugated to the anionic tripeptide glutathione (GSH), glucuronic acid, or sulfate.. Because MRP1 transports oxidized GSH, glutathione disulfide, it is believed to play additional roles in maintaining GSH homeostasis and regulating the redox state of cells.. It can transport a variety of drugs, endogenous metabolites, xenobiotics, and hydrophobic drugs or other compounds that are conjugated to the anionic tripeptide glutathione (GSH), glucuronic acid, or sulfate. Because MRP1 transports oxidized GSH, glutathione disulfide, it is believed to play additional roles in maintaining GSH homeostasis and regulating the redox state of cells. The role of MRPs in BBB permeability has been demonstrated by experiments in which inhibitors of MRPs, such as probenecid or MK-571, were shown to enhance drug penetration into the brain or to inhibit drug efflux from isolated brain endothelial cells.
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