Evaluation of [11C]laniquidar as a tracer of P-glycoprotein: radiosynthesis and biodistribution in rats

Luurtsema, Gert; Schuit, Robert C.; Klok, Rob P.; Verbeek, Joost; Leysen, Josée E.; Lammertsma, Adriaan A.; Windhorst, Albert D.

doi:10.1016/j.nucmedbio.2009.03.004

Cited by 62 publications

(63 citation statements)

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“…This metabolic profile of 11 C-laniquidar in humans is different from that in rats, for which 68% of parent 11 C-laniquidar was still present at 30 min after tracer injection (10). The present findings, however, were not completely unexpected, as laniquidar is radiolabeled at the ester moiety, and methyl esters are known to be unstable in vivo (10) due to esterases in the blood.…”

Section: Discussioncontrasting

confidence: 57%

“…Synthesis of 11 C-Laniquidar 11 C-laniquidar was synthesized as described previously (10,11) in a good-manufacturing-practice-compliant manner. 11 C-laniquidar was obtained as a sterile and pyrogen-free solution for intravenous injection in a yield of 800-1,700 MBq, a specific activity of 20-135 GBqÁmmol 21 , and a radiochemical purity greater than 98%.…”

Section: Mr Imagingmentioning

confidence: 99%

“…Third-generation P-glycoprotein inhibitors, such as laniquidar, elacridar, and tariquidar, have recently been labeled with 11 C (8-10). Unfortunately, initial studies on uptake of 11 C-laniquidar in the rat brain have been inconclusive (10), and to date only a biodistribution study has been performed in humans (11). The purposes of the present study were to develop a tracer kinetic model for quantification of 11 C-laniquidar kinetics in the brain of healthy volunteers and to define test-retest variability of the most appropriate outcome measure.…”

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confidence: 99%

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Quantification of ¹¹C-Laniquidar Kinetics in the Brain

et al. 2015

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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. Timeactivity 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 Claniquidar 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 K 1 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 (K 1 ) 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, K 1 could be obtained from a 5-min scan using a standard 1T1K model. In both cases, the test-retest variability of K 1 was approximately 19%.

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confidence: 57%

Section: Mr Imagingmentioning

confidence: 99%

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Quantification of ¹¹C-Laniquidar Kinetics in the Brain

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“…2 Much research attention has been focused on the discovery and development of agents that can inhibit P-glycoprotein with high efficiency and low toxicity. [3][4][5] However, these compounds, with their low efficiency and/or high toxicity, are often nonspecific. 6,7 The first and second generations of P-glycoprotein inhibitors have now been tested in clinic trials, but their therapeutic effects and safety profiles have not been ideal.…”

Section: Introductionmentioning

confidence: 99%

Effect of magnetic nanoparticles of Fe3O4 and wogonin on the reversal of multidrug resistance in K562/A02 cell line

Chen¹

2012

IJN

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Background: Multidrug resistance is the main obstacle to the efficiency of systemic chemotherapy against hematologic malignancy. This study investigated the reversible effect of the copolymer wogonin and daunorubicin coloaded into Fe 3 O 4 magnetic nanoparticles, and the mechanism potentially involved. Methods: The growth inhibition rate of K562/A02 cells was investigated by MTT assay, and apoptosis of cells and the intracellular daunorubicin concentration were detected by flow cytometry. Distribution of nanoparticles taken up by K562/A02 cells was observed under a transmission electron microscope and demonstrated by Prussian blue staining. The transcription level of MDR1 mRNA and expression of P-glycoprotein were determined by reverse transcriptase polymerase chain reaction and Western blotting assay, respectively. Results: The reversible effect of daunorubicin-wogonin magnetic nanoparticles was 8.87-fold that of daunorubicin + wogonin and of daunorubicin magnetic nanoparticles. Transmission electron microscopy and Prussian blue staining revealed that the nanoparticles were located in the endosome vesicles of cytoplasm. Also, the apoptosis rate and accumulation of intracellular daunorubicin in the daunorubicin-wogonin magnetic nanoparticle group were significantly higher than that in the daunorubicin, daunorubicin + wogonin, and daunorubicin magnetic nanoparticle groups. Furthermore, transcription of MDR1 mRNA and expression of P-glycoprotein in K562/ A02 cells were significantly downregulated in the daunorubicin-wogonin magnetic nanoparticle group compared with the other groups. Conclusion: These findings suggest that the remarkable effects of the novel daunorubicinwogonin magnetic nanoparticle formulation on multidrug resistant K562/A02 leukemia cells would be a promising strategy for overcoming multidrug resistance.

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“…Laniquidar is an inhibitor of P-gp (9) and therefore should bind proportionally to P-gp density. Recently, this compound was labeled with 11 C and its biodistribution in rats was evaluated (10). Previously, however, metabolic profiles for the P-gp substrate tracer (R)-11 C-verapamil were shown to differ substantially between species (11,12), as may also be the case for 11 C-laniquidar.…”

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Radiation Dose of the P-Glycoprotein Tracer¹¹C-Laniquidar

et al. 2013

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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 Claniquidar was seen in liver, spleen, kidneys, and lung, whereas brain uptake was low. The effective dose for 11 C-laniquidar was 4.76 6 0.13 and 3.69 6 0.01 mSvÁMBq 21 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.Key Words: P-glycoprotein; PET; 11 C-laniquidar; dosimetry; multidrug transporter Nucl Med 2013; 54:2101 54: -2103 54: DOI: 10.2967 Resi stance to drug therapy affects approximately 30% of all patients with epilepsy (1) and may be due, at least in part, to decreased passage of antiepileptic drugs across the blood-brain barrier. Uptake and efflux drug transporters play a major functional role in regulating drug entry into the brain. Two large and important drug transporter families are the organic anion-transporting polypeptide (OATP) family and the adenosine triphosphate-binding cassette transporter superfamily (2,3). Several members of both families are expressed at the human blood-brain barrier, including OATP1A2, OATP1C1, and OATP3A1 (members of the OATP family) and P-glycoprotein (P-gp), breast cancer resistance protein, and multidrug resistance protein 4 (members of the adenosine triphosphate-binding transporter superfamily) (2,3). In this paper, the focus is on the most widely studied efflux transporter, P-gp. It has been proposed that changes in P-gp expression or function at the blood-brain barrier play an important role in pharmacoresistance in epilepsy (4). The multidrug transporter P-gp and other efflux transporters actively transport substrates, including many central nervous system drugs, against a concentration gradient from brain to blood and cerebrospinal fluid. Hence, overexpression or increased activity of the transporter system may result in reduced tissue concentrations of central nervous system drugs in the brain, thereby greatly limiting their therapeutic efficacy. There are two case reports suggesting that inhibiting P-gp in medically refractory epilepsy patients decreases seizure frequency, at least temporarily (5,6). P-gp functionality can be assessed in vivo by means of (R)-11 C-verapamil and 11 C-N-desmethyllo...

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Evaluation of [11C]laniquidar as a tracer of P-glycoprotein: radiosynthesis and biodistribution in rats

Cited by 62 publications

References 35 publications

Quantification of ¹¹C-Laniquidar Kinetics in the Brain

Quantification of ¹¹C-Laniquidar Kinetics in the Brain

Effect of magnetic nanoparticles of Fe3O4 and wogonin on the reversal of multidrug resistance in K562/A02 cell line

Radiation Dose of the P-Glycoprotein Tracer¹¹C-Laniquidar

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Evaluation of [11C]laniquidar as a tracer of P-glycoprotein: radiosynthesis and biodistribution in rats

Cited by 62 publications

References 35 publications

Quantification of 11C-Laniquidar Kinetics in the Brain

Quantification of 11C-Laniquidar Kinetics in the Brain

Effect of magnetic nanoparticles of Fe3O4 and wogonin on the reversal of multidrug resistance in K562/A02 cell line

Radiation Dose of the P-Glycoprotein Tracer11C-Laniquidar

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Quantification of ¹¹C-Laniquidar Kinetics in the Brain

Quantification of ¹¹C-Laniquidar Kinetics in the Brain

Radiation Dose of the P-Glycoprotein Tracer¹¹C-Laniquidar