RESULTS:
1 - 4 of 4 for ""[11C]verapamil""
Substrates, Inhibitors and Activators of P-glycoprotein: Candidates for Radiolabeling and Imaging Perspectives
In recent years several PET tracers for monitoring the activity and expression of P-gp at the BBB have been tested. P-gp substrates such as [11C]verapamil and [11C]loperamide can be employed to visualize P-gp activity but they display a moderate baseline uptake in the brain and formation of radiolabeled metabolites which hamper the interpretation of PET data. P-gp inhibitors such as [11C]elacridar [11C]laniquidar and [11C]tariquidar have been tested to investigate Pgp expression and the results need further investigation. Recently we developed MC18 MC266 and MC80 that have been characterized as an inhibitor substrate and inducer of P-gp both by in vitro assays and in the everted gut sac method. These compounds have been radiolabelled with 11C and been evaluated in vivo. In the present review we compare the outcome of biological in vitro assays and the corresponding in vivo PET data for the P-gp inhibitors [11C]MC18 and [11C]elacridar the P-gp substrates [11C]MC266 and [11C]verapamil the P-gp inducer [11C]MC80 and the P-gp modulator cyclosporin A. Since a satisfactory overlap was found comparing in vivo results and the corresponding in vitro findings the proposed biological in vitro assays could be predictive for the in vivo PET data of novel radiotracers. PET tracers could be employed for various purposes: radiolabeled P-gp inhibitors to monitor decreased expression of P-gp at the BBB in neurodegenerative disorders such as Alzheimer's and Parkinson's disease; and radiolabeled P-gp substrates with a high baseline uptake to monitor increased expression of P-gp in epileptic foci.
PET Imaging of MRP1 Function in the Living Brain: Method Development and Future Perspectives
Multidrug resistance-associated protein 1 (MRP1) functions as a primary active transporter utilizing energy from ATP hydrolysis. In the central nervous system (CNS) MRP1 plays an important role in limiting the permeation of xenobiotic and endogenous substrates across the blood-brain and blood-cerebrospinal fluid barriers and across brain parenchymal cells. While MRP1 contributes to minimizing the neurotoxic effects of drugs it may also restrict the distribution of drugs for the treatment of CNS diseases. Moreover neurodegenerative disease may be associated with abnormal expression of efflux transporters in the brain. Noninvasive measurement of MRP1 function will therefore be useful for directly evaluating the effect of modulators on enhancing the penetration of drugs into the brain and for examining the pathophysiological role of MRP1 in the brain. Positron emission tomography (PET) is a powerful molecular imaging technique. While several PET probes have been proposed for imaging function of the efflux transporter P-glycoprotein few reports discuss the probes for imaging MRP1 function in the brain. Ideally brain radioactivity should consist of a single radioactive compound that is selectively transported by the efflux transporter of interest without other efflux routes. However most PET probes for MRP1 or P-glycoprotein are eliminated by both a transporter and simple diffusion resulting in inaccurate measurement of pump function. This review addresses a new strategy to avoid this problem and suggests the design of a PET probe based on this strategy particularly for MRP1 imaging. Several published reports on imaging MRP1 function with PET are also discussed.
Carbon-11 Labeled Tracers for In Vivo Imaging of P-Glycoprotein Function: Kinetics, Advantages and Disadvantages
P-glycoprotein (P-gp) is a drug efflux transporter with broad substrate specificity localized in the blood-brain barrier and in several peripheral organs. In order to understand the role of P-gp in physiological and patho-physiological conditions several carbon-11 labelled P-gp tracers have been developed and validated. This review provides an overview of the spectrum of radiopharmaceuticals that is available for this purpose. A short overview of the physiology of the blood-brain barrier in health and disease is also provided. Tracer kinetic modelling for quantitative analysis of P-gp function and expression is highlighted and the advantages and disadvantages of the various tracers are discussed.
PET-Evaluated Transport of [11C]Hydroxyurea Across the Rat Blood-Brain Barrier - Lack of Influence of Cyclosporin and Probenecid
The transport of hydroxyurea a ribonucleoside reductase inhibitor over biological membranes is slow and it has therefore been suggested that the substance could interact with an active efflux transporter. The transport of [11C]hydroxyurea into the rat brain was therefore studied after administration of the multidrug resistance protein inhibitor probenecid (50 and 150 mg/kg) the P-glycoprotein inhibitor cyclosporin A (25 mg/kg) hydroxyurea (50 150 and 450 mg/kg) and mannitol (25%). None of the intervention drugs affected the brain uptake of [11C]hydroxyurea. The brain-toplasma concentration ratios (Kp) with or without intervention drug were in the range 0.12-0.25 after 60 min of [11C]hydroxyurea infusion. [11C]Verapamil a P-glycoprotein substrate with low brain penetration was used to study the ability of hydroxyurea to inhibit P-glycoprotein. Administration of hydroxyurea (150 and 450 mg/kg) did not increase brain concentrations of [11C]verapamil. It is therefore unlikely that hydroxyurea is a substrate for or an inhibitor of Pglycoprotein or a substrate for a probenecid sensitive transport system. The low brain concentrations may instead be the result of slow uptake due to the hydrophilic nature of hydroxyurea.