ABSTRACT
The design, synthesis, in vitro inhibitory potency, and pharmacokinetic (PK) profiles of Ko143 analogs are described. Compared to commonly used Ko143, the new breast cancer resistance protein (BCRP) inhibitor (compound A) showed the same potency and a significantly improved PK profile in rats (lower clearance [1.54L/h/kg] and higher bioavailability [123%]). Ko143 on the other hand suffers from poor bioavailability. Compared to Ko143, compound A would be a useful probe for delineating the role of BCRP during in vivo studies in animals.
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , Diketopiperazines/chemical synthesis , Diketopiperazines/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Animals , Caco-2 Cells , Estrone/analogs & derivatives , Estrone/metabolism , Heterocyclic Compounds, 4 or More Rings/blood , Humans , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Bexarotene (Targretin) is a retinoid X receptor (RXR) agonist that has applications for treatment of T cell lymphoma and proposed mechanisms of action in Alzheimer's disease that have been the subject of recent controversy. Carbon-11 labeled bexarotene ([(11)C-carbonyl]4-[1-(3,5,5,8,8-pentamethyltetralin-2-yl)ethenyl]benzoic acid) was synthesized using a Cu-mediated cross-coupling reaction employing an arylboronate precursor 1 and [(11)C]carbon dioxide under atmospheric pressure in 15 ± 2% uncorrected radiochemical yield (n = 3), based on [(11)C]CO2. Judicious choice of solvents, catalysts, and additives, as well as precursor concentration and purity of [(11)C]CO2, enabled the preparation of this (11)C-labeled carboxylic acid. Formulated [(11)C]bexarotene was isolated (>37 mCi) with >99% radiochemical purity in 32 min. Preliminary positron emission tomography-magnetic resonance imaging revealed rapid brain uptake in nonhuman primate in the first 75 s following intravenous administration of the radiotracer (specific activity >0.3 Ci/µmol at time of injection), followed by slow clearance (Δ = -43%) over 60 min. Modest uptake (SUVmax = 0.8) was observed in whole brain and regions with high RXR expression.
ABSTRACT
Much of our fundamental knowledge related to polymer networks is built on an assumption of ideal end-linked network structure. Real networks invariably possess topological imperfections that negatively affect mechanical properties; modifications of classical network theories have been developed to account for these defects. Despite decades of effort, there are no known experimental protocols for precise quantification of even the simplest topological network imperfections: primary loops. Here we present a simple conceptual framework that enables primary loop quantification in polymeric materials. We apply this framework to measure the fraction of primary loop junctions in trifunctional PEG-based hydrogels. We anticipate that the concepts described here will open new avenues of theoretical and experimental research related to polymer network structure.
