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Journal of Nuclear Medicine : Official... Nov 2015Overexpression of the multidrug efflux transport P-glycoprotein may play an important role in pharmacoresistance. (11)C-laniquidar is a newly developed tracer of...
UNLABELLED
Overexpression of the multidrug efflux transport P-glycoprotein may play an important role in pharmacoresistance. (11)C-laniquidar is a newly developed tracer of P-glycoprotein expression. The aim of this study was to develop a pharmacokinetic model for quantification of (11)C-laniquidar uptake and to assess its test-retest variability.
METHODS
Two (test-retest) dynamic (11)C-laniquidar PET scans were obtained in 8 healthy subjects. Plasma input functions were obtained using online arterial blood sampling with metabolite corrections derived from manual samples. Coregistered T1 MR images were used for region-of-interest definition. Time-activity curves were analyzed using various plasma input compartmental models.
RESULTS
(11)C-laniquidar was metabolized rapidly, with a parent plasma fraction of 50% at 10 min after tracer injection. In addition, the first-pass extraction of (11)C-laniquidar was low. (11)C-laniquidar time-activity curves were best fitted to an irreversible single-tissue compartment (1T1K) model using conventional models. Nevertheless, significantly better fits were obtained using 2 parallel single-tissue compartments, one for parent tracer and the other for labeled metabolites (dual-input model). Robust K1 results were also obtained by fitting the first 5 min of PET data to the 1T1K model, at least when 60-min plasma input data were used. For both models, the test-retest variability of (11)C-laniquidar rate constant for transfer from arterial plasma to tissue (K1) was approximately 19%.
CONCLUSION
The accurate quantification of (11)C-laniquidar kinetics in the brain is hampered by its fast metabolism and the likelihood that labeled metabolites enter the brain. Best fits for the entire 60 min of data were obtained using a dual-input model, accounting for uptake of (11)C-laniquidar and its labeled metabolites. Alternatively, K1 could be obtained from a 5-min scan using a standard 1T1K model. In both cases, the test-retest variability of K1 was approximately 19%.
Topics: ATP Binding Cassette Transporter, Subfamily B; Adult; Benzazepines; Biotransformation; Brain; Carbon Radioisotopes; Female; Healthy Volunteers; Humans; Isotope Labeling; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Quinolines; Radiopharmaceuticals; Reproducibility of Results; Young Adult
PubMed: 26294297
DOI: 10.2967/jnumed.115.157586 -
Journal of Nuclear Medicine : Official... Dec 2013Resistance to current drug therapy is an important issue in the treatment of epilepsy. Inadequate access of central nervous system drugs to their targets in the brain... (Clinical Trial)
Clinical Trial
UNLABELLED
Resistance to current drug therapy is an important issue in the treatment of epilepsy. Inadequate access of central nervous system drugs to their targets in the brain may be caused by overexpression or overactivity of multidrug transporters, such as P-glycoprotein (P-gp), at the blood-brain barrier. Laniquidar, an inhibitor of P-gp, has been labeled with (11)C for use in PET studies of P-gp expression in humans. Given potential interspecies differences in biodistribution, the purpose of this study was to ensure safe use of (11)C-laniquidar by determining the dosimetry of (11)C-laniquidar using whole-body PET studies.
METHODS
Six healthy volunteers were subjected to a series of 10 whole-body PET scans within approximately 70 min. Five blood samples were taken during the series.
RESULTS
High uptake of (11)C-laniquidar was seen in liver, spleen, kidneys, and lung, whereas brain uptake was low. The effective dose for (11)C-laniquidar was 4.76 ± 0.13 and 3.69 ± 0.01 μSv·MBq(-1) for women and men, respectively.
CONCLUSION
Biodistribution and measured effective dose indicate that (11)C-laniquidar is a safe tracer for PET imaging, with a total dose of about 2 mSv for a brain PET/CT protocol.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adult; Benzazepines; Carbon Radioisotopes; Female; Humans; Male; Quinolines; Radiation Dosage; Radioactive Tracers; Radiometry
PubMed: 24092938
DOI: 10.2967/jnumed.113.120857 -
Nuclear Medicine and Biology Aug 2009At present, P-glycoprotein (P-gp) function can be studied using positron emission tomography (PET) together with a labelled P-gp substrate such as R-[11C]verapamil. Such...
At present, P-glycoprotein (P-gp) function can be studied using positron emission tomography (PET) together with a labelled P-gp substrate such as R-[11C]verapamil. Such a tracer is, however, less suitable for investigating P-gp (over)expression. Laniquidar is a third-generation P-gp inhibitor, which has been used in clinic trials for modulating multidrug resistance transporters. The purpose of the present study was to develop the radiosynthesis of [11C]laniquidar and to assess its suitability as a tracer of P-gp expression. The radiosynthesis of [11C]laniquidar was performed by methylation of the carboxylic acid precursor with [11C]CH3I. The product was purified by HPLC and reformulated over a tC18 Seppak, yielding a sterile solution of [11C]laniquidar in saline. For evaluating [11C]laniquidar, rats were injected with 20 MBq [11C]laniquidar via a tail vein and sacrificed at 5, 15, 30 and 60 min after injection. Several tissues and distinct brain regions were dissected and counted for radioactivity. In addition, uptake of [11C]laniquidar in rats pretreated with cyclosporine A and valspodar (PSC 833) was determined at 30 min after injection. Finally, the metabolic profile of [11C]laniquidar in plasma was determined. [11C]Laniquidar could be synthesized in moderate yields with high specific activity. Uptake in brain was low, but significantly increased after administration of cyclosporine A. Valspodar did not have any effect on cerebral uptake of [11C]laniquidar. In vivo rate of metabolism was relatively low. Further kinetic studies are needed to investigate the antagonistic behaviour of [11C]laniquidar at tracer level.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Benzazepines; Binding, Competitive; Carbon Radioisotopes; Cyclosporine; Cyclosporins; Quinolines; Radioactive Tracers; Rats; Rats, Wistar; Tissue Distribution
PubMed: 19647170
DOI: 10.1016/j.nucmedbio.2009.03.004 -
Nuclear Medicine and Biology Jan 2012An earlier report suggested that mass amount of PET tracers could be an important factor in brain uptake mediated by P-glycoprotein. Thereby, this study investigated the... (Comparative Study)
Comparative Study
INTRODUCTION
An earlier report suggested that mass amount of PET tracers could be an important factor in brain uptake mediated by P-glycoprotein. Thereby, this study investigated the influence of mass dose of laniquidar, desmethyl-loperamide and loperamide on the P-glycoprotein-mediated brain uptake of, respectively, [(11)C]-laniquidar and [(11)C]-N-desmethyl-loperamide ([(11)C]-dLop).
METHODS
Wild-type (WT) mice were injected intravenously with solutions of 5.6 MBq [(11)C]-laniquidar (either no carrier added or 60 mg/kg laniquidar added) or with 5.0-7.4 MBq [(11)C]-dLop (either no carrier added or 3 mg/kg desmethyl loperamide). Mice were killed, and brain and blood were collected, weighted and counted for radioactivity. Mdr1a(-/-) knockout mice were incorporated as the control group.
RESULTS
Injection of (11)C-laniquidar (no carrier added) in WT mice resulted in a statistical significant lower brain uptake (0.7±0.2 %ID/g) compared to the carrier-added formulation (60 mg/kg laniquidar) (3.1±0.3 %ID/g) (P=.004), while no statistical difference could be observed between formulations of [(11)C]-dLop. The [(11)C]-laniquidar and [(11)C]-dLop blood concentrations were not significantly different between the tested formulations in WT mice. In control animals, no effect of mass amount on brain uptake of both tracers could be demonstrated.
CONCLUSIONS
These results demonstrate the bivalent character of laniquidar, acting as a substrate at low doses and as a blocking agent for P-glycoprotein transport in the brain at higher doses. In comparison, no difference was observed in [(11)C]-dLop uptake between carrier- and no-carrier-added formulations, which confirms that desmethyl-loperamide is a substrate of P-glycoprotein at the blood-brain barrier.
Topics: ATP Binding Cassette Transporter, Subfamily B; Animals; Antidiarrheals; Benzazepines; Biological Transport; Blood-Brain Barrier; Brain; Carbon Radioisotopes; Case-Control Studies; Drug Carriers; Loperamide; Male; Mice; Mice, Knockout; Quinolines; Tissue Distribution
PubMed: 21958857
DOI: 10.1016/j.nucmedbio.2011.06.009 -
Nuclear Medicine and Biology Aug 2013To analyse the impact of both epilepsy and pharmacological modulation of P-glycoprotein on brain uptake and kinetics of positron emission tomography (PET) radiotracers...
INTRODUCTION
To analyse the impact of both epilepsy and pharmacological modulation of P-glycoprotein on brain uptake and kinetics of positron emission tomography (PET) radiotracers [(11)C]quinidine and [(11)C]laniquidar.
METHODS
Metabolism and brain kinetics of both [(11)C]quinidine and [(11)C]laniquidar were assessed in naive rats, electrode-implanted control rats, and rats with spontaneous recurrent seizures. The latter group was further classified according to their response to the antiepileptic drug phenobarbital into "responders" and "non-responders". Additional experiments were performed following pre-treatment with the P-glycoprotein modulator tariquidar.
RESULTS
[(11)C]quinidine was metabolized rapidly, whereas [(11)C]laniquidar was more stable. Brain concentrations of both radiotracers remained at relatively low levels at baseline conditions. Tariquidar pre-treatment resulted in significant increases of [(11)C]quinidine and [(11)C]laniquidar brain concentrations. In the epileptic subgroup "non-responders", brain uptake of [(11)C]quinidine in selected brain regions reached higher levels than in electrode-implanted control rats. However, the relative response to tariquidar did not differ between groups with full blockade of P-glycoprotein by 15 mg/kg of tariquidar. For [(11)C]laniquidar differences between epileptic and control animals were only evident at baseline conditions but not after tariquidar pretreatment.
CONCLUSIONS
We confirmed that both [(11)C]quinidine and [(11)C]laniquidar are P-glycoprotein substrates. At full P-gp blockade, tariquidar pre-treatment only demonstrated slight differences for [(11)C]quinidine between drug-resistant and drug-sensitive animals.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Benzazepines; Carbon Radioisotopes; Chronic Disease; Disease Models, Animal; Epilepsy; Female; Gene Expression Regulation; Kinetics; Male; Phenobarbital; Positron-Emission Tomography; Quinidine; Quinolines; Radiochemistry; Rats; Rats, Sprague-Dawley; Recurrence; Treatment Outcome
PubMed: 23827307
DOI: 10.1016/j.nucmedbio.2013.05.008 -
Current Drug Targets Jul 2006Multidrug resistance (MDR) is a major obstacle to the effective treatment of cancer. One of the underlying mechanisms of MDR is cellular overproduction of P-glycoprotein... (Review)
Review
Multidrug resistance (MDR) is a major obstacle to the effective treatment of cancer. One of the underlying mechanisms of MDR is cellular overproduction of P-glycoprotein (P-gp) which acts as an efflux pump for various anticancer drugs. P-gp is encoded by the MDR1 gene and its overexpression in cancer cells has become a therapeutic target for circumventing multidrug resistance. A potential strategy is to co-administer efflux pump inhibitors, although such reversal agents might actually increase the side effects of chemotherapy by blocking physiological anticancer drug efflux from normal cells. Although many efforts to overcome MDR have been made using first and second generation reversal agents comprising drugs already in current clinical use for other indications (e.g. verapamil, cyclosporine A, quinidine) or analogues of the first-generation drugs (e.g. dexverapamil, valspodar, cinchonine), few significant advances have been made. Clinical trials with third generation modulators (e.g. biricodar, zosuquidar, and laniquidar) specifically developed for MDR reversal are ongoing. The results however are not encouraging and it may be that the perfect reverser does not exist. Other approaches to multidrug resistance reversal have also been considered: encapsulation of anthracyclines in liposomes or other carriers which deliver these drugs selectively to tumor tissues, the use of P-gp targeted antibodies such as UIC2 or the use of antisense strategies targeting the MDR1 messenger RNA. More recently, the development of transcriptional regulators appears promising. Also anticancer drugs that belong structurally to classes of drugs extruded from cells by P-gp but that are not substrates of this drug transporter may act as potent inhibitors of MDR tumors (e.g. epothilones, second generation taxanes). Taking advantage of MDR has also been studied. Bone marrow suppression, one of the major side effects of cancer chemotherapy, can compromise the potential of curative and palliative chemotherapy. It is conceivable that drug resistance gene transfer into bone marrow stem cells may be able to reduce or abolish chemotherapy-induced myelosuppression and facilitate the use of high dose chemotherapy. Clinical trials of retroviral vectors containing drug resistance genes have established that the approach is safe and are now being designed to address the therapeutically relevant issues.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Clinical Trials as Topic; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Membrane Transport Modulators; Molecular Structure; Neoplasms
PubMed: 16842217
DOI: 10.2174/138945006777709593 -
European Journal of Medicinal Chemistry Sep 2017The biggest challenge associated with cancer chemotherapy is the development of cross multi-drug resistance to almost all anti-cancer agents upon chronic treatment. The... (Review)
Review
The biggest challenge associated with cancer chemotherapy is the development of cross multi-drug resistance to almost all anti-cancer agents upon chronic treatment. The major contributing factor for this resistance is efflux of the drugs by the p-glycoprotein pump. Over the years, inhibitors of this pump have been discovered to administer them in combination with chemotherapeutic agents. The clinical failure of first and second generation P-gp inhibitors (such as verapamil and cyclosporine analogs) has led to the discovery of third generation potent P-gp inhibitors (tariquidar, zosuquidar, laniquidar). Most of these inhibitors are nitrogenous compounds and recently a natural alkaloid CBT-01 (tetrandrine) has advanced to the clinical phase. CBT-01 demonstrated positive results in Phase-I study in combination with paclitaxel, which warranted conducting it's Phase II/III trial. Apart from this, there exist a large number of natural alkaloids possessing potent inhibition of P-gp efflux pump and other related pumps responsible for the development of resistance. Despite the extensive contribution of alkaloids in this area, has never been reviewed. The present review provides a comprehensive account on natural alkaloids possessing P-gp inhibition activity and their potential for multidrug resistance reversal in cancer.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Alkaloids; Antineoplastic Agents, Phytogenic; Biological Products; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Molecular Structure; Neoplasms; Structure-Activity Relationship
PubMed: 28675836
DOI: 10.1016/j.ejmech.2017.06.047 -
Expert Review of Clinical Pharmacology May 2008The development of novel efflux pump inhibitors is an emerging and challenging research field. Besides the use of such excipients in cancer therapy, efflux pump...
The development of novel efflux pump inhibitors is an emerging and challenging research field. Besides the use of such excipients in cancer therapy, efflux pump inhibitors are gaining increasing interest with regards to drug delivery. In particular, inhibition of efflux pumps located in the intestine and the blood-brain barrier offers promising prospects. Nowadays, third-generation inhibitors, such as elacridar, zosuquidar, laniquidar, OC144-093 and tariquidar, have been evaluated in clinical trials. Apart from these small, molecular inhibitors, which will be discussed within the current review, a focus has been set on polymeric or polymer-based inhibitors, including poly(ethylene glycol) and derivatives, poloxamers and thiomers.
PubMed: 24422696
DOI: 10.1586/17512433.1.3.429 -
Current Pharmaceutical Design 2016P-glycoprotein function is associated with a number of neurodegenerative and psychiatric diseases as well as with pharmacoresistance to for example antiepileptic drugs.... (Review)
Review
P-glycoprotein function is associated with a number of neurodegenerative and psychiatric diseases as well as with pharmacoresistance to for example antiepileptic drugs. The ability to measure P-gp function in vivo would allow for an increased understanding of the mechanisms of disease and treatment. This review assesses the various approaches to in vivo quantification of P-gp function using currently available P-gp tracers and PET in humans. First, the use of compartment models, and their interpretation in terms of P-gp function at the blood-brain barrier, is discussed. Then, the methods that have been used to quantify PET data of the P-gp tracers [11C]verapamil, [11C]N-desmetyl-loperamide (dLop), [11C]laniquidar, [11C]phenytoin, [11C]tariquidar and [11C]elacridar are reviewed. In summary, the extraction of P-gp substrate PET tracers, which is their plasma to tissue rate constant K corrected for variations in regional cerebral blood flow, is generally considered to be the preferred measure of P-gp function.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Blood-Brain Barrier; Humans; Kinetics; Models, Biological; Positron-Emission Tomography
PubMed: 27494063
DOI: 10.2174/1381612822666160804093852