Development of Fluorine-18 Labeled Metabolically Activated Tracers for Imaging of Drug Efflux Transporters with Positron Emission Tomography

Sander, Kerstin; Galante, Eva; Gendron, Thibault; Yiannaki, Elena; Patel, Niral; Kalber, Tammy L.; Badar, Adam; Robson, Mathew; Johnson, Sean Peter; Bauer, Florian; Mairinger, Severin; Stanek, Johann; Wanek, Thomas; Kuntner, Claudia; Kottke, Tim; Weizel, Lilia; Dickens, David; Erlandsson, Kjell; Hutton, Brian F.; Lythgoe, Mark F.; Stark, Holger; Langer, Oliver; Koepp, Matthias J.; Årstad, Erik

doi:10.1021/acs.jmedchem.5b00652

Cited by 19 publications

(8 citation statements)

References 58 publications

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“…Since the development of S N 2 reactions with [ 18 F]fluoride more than 30 years ago, continuous efforts have been made to expand the radiochemical space. − Recent chemical insights have re-invigorated the field and led to the discovery of several innovative strategies for radiofluorination. New types of precursors, including aryl boronic acids and esters, − preformed Pd IV or Ni II complexes, , N -arylsydnones, uronium salts, iodonium ylides, , and arylsulfonium salts, − now allow direct fluorination of aromatic ring systems that until recently were beyond reach. While these methods certainly have expanded the radiochemical space, their impact on clinical PET remains limited .…”

Section: Introductionmentioning

confidence: 99%

Ring-Closing Synthesis of Dibenzothiophene Sulfonium Salts and Their Use as Leaving Groups for Aromatic ¹⁸F-Fluorination

et al. 2018

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Herein, we report a novel intramolecular ring-closing reaction of biaryl thioethers that give access to highly functionalized dibenzothiophene sulfonium salts under mild conditions. The resulting precursors react regioselectively with [18F]fluoride to give [18F]fluoroarenes in predictable radiochemical yields. The strategy expands the available radiochemical space and provides superior labeling efficiency for clinically relevant PET tracers.

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Section: Introductionmentioning

confidence: 99%

Ring-Closing Synthesis of Dibenzothiophene Sulfonium Salts and Their Use as Leaving Groups for Aromatic ¹⁸F-Fluorination

et al. 2018

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“…Because of limited baseline uptake (in the presence of P-gp) or the presence of brain radiometabolites, available PET radioligands do not allow for accurate estimation of the brain efflux constant (k 2 ). Therefore, alternative PET radiotracers with optimized pharmacokinetic properties are needed to investigate the k 2 component of P-gp function and its overall contribution to the brain distribution (V T ) (6,10).…”

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confidence: 99%

Imaging the Impact of the P-Glycoprotein (ABCB1) Function on the Brain Kinetics of Metoclopramide

Pottier¹,

Marie²,

Goutal³

et al. 2015

J Nucl Med

105

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The effects of metoclopramide on the central nervous system (CNS) in patients suggest substantial brain distribution. Previous data suggest that metoclopramide brain kinetics may nonetheless be controlled by ATP-binding cassette (ABC) transporters expressed at the blood-brain barrier. We used 11 C-metoclopramide PET imaging to elucidate the kinetic impact of transporter function on metoclopramide exposure to the brain. Methods: 11 C-metoclopramide transport by P-glycoprotein (P-gp; ABCB1) and the breast cancer resistance protein (BCRP; ABCG2) was tested using uptake assays in cells overexpressing P-gp and BCRP. 11 C-metoclopramide brain kinetics were compared using PET in rats (n 5 4-5) in the absence and presence of a pharmacologic dose of metoclopramide (3 mg/kg), with or without P-gp inhibition using intravenous tariquidar (8 mg/kg). The 11 C-metoclopramide brain distribution (V T based on Logan plot analysis) and brain kinetics (2-tissue-compartment model) were characterized with either a measured or an imaged-derived input function. Plasma and brain radiometabolites were studied using radio-high-performance liquid chromatography analysis. Results: 11 C-metoclopramide transport was selective for P-gp over BCRP. Pharmacologic dose did not affect baseline 11 C-metoclopramide brain kinetics (V T 5 2.28 ± 0.32 and 2.04 ± 0.19 mL⋅cm −3 using microdose and pharmacologic dose, respectively). Tariquidar significantly enhanced microdose 11 C-metoclopramide V T (7.80 ± 1.43 mL⋅cm −3 ) with a 4.4-fold increase in K 1 (influx rate constant) and a 2.3-fold increase in binding potential (k 3 /k 4 ) in the 2-tissue-compartment model. In the pharmacologic situation, P-gp inhibition significantly increased metoclopramide brain distribution (V T 5 6.28 ± 0.48 mL⋅cm −3 ) with a 2.0-fold increase in K 1 and a 2.2-fold decrease in k 2 (efflux rate), with no significant impact on binding potential. In this situation, only parent 11 C-metoclopramide could be detected in the brains of P-gp-inhibited rats. Conclusion: 11 C-metoclopramide benefits from favorable pharmacokinetic properties that offer reliable quantification of P-gp function at the blood-brain barrier in a pharmacologic situation. Using metoclopramide as a model of CNS drug, we demonstrated that P-gp function not only reduces influx but also mediates the efflux from the brain back to the blood compartment, with additional impact on brain distribution. This PET-based strategy of P-gp function investigation may provide new insight on the contribution of P-gp to the variability of response to CNS drugs between patients.

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“…Electrospray ionization mass spectrometry (ESI-MS) was carried out using a Bruker microTOF-Q instrument in positive ion mode (capillary potential of 4500 V). QC analysis was performed using an HPLC system of Jasco (Easton, MD, USA) containing a PU-2089 pump station equipped with a Varian Kromasil C18 column ( (10). To a stirred solution of 2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile (9, 3.83 g, 17.5 mmol) in 60 mL of dry DCM was added sodium hydride (60% dispersion in mineral oil; 1.40 g, 34.9 mmol), and the mixture was heated to 65 °C.…”

Section: ■ Methodsmentioning

confidence: 99%

“…Although the proof-of-concept was successful, slow rates of enzymatic conversion toward the prodrug tracer did not give the anticipated results. 10 Another study proposed three new fluorine-18 labeled P-gp tracers. Only one of the three showed P-gp substrate functionality in vivo , although all tracers were evaluated as substrates in vitro .…”

Section: Introductionmentioning

confidence: 99%

“…In another comprehensive study of Sander et al, fluorine-18 labeled tracers were used in a new approach to metabolically activate a dual P-gp/BCRP substrate. Although the proof-of-concept was successful, slow rates of enzymatic conversion toward the prodrug tracer did not give the anticipated results . Another study proposed three new fluorine-18 labeled P-gp tracers.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Evaluation of New Fluorine-18 Labeled Verapamil Analogs To Investigate the Function of P-Glycoprotein in the Blood–Brain Barrier

Raaphorst

Luurtsema

Schuit

et al. 2017

ACS Chem. Neurosci.

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P-glycoprotein is an efflux transporter located in the blood–brain barrier. (R)-[11C]Verapamil is widely used as a PET tracer to investigate its function in patients with epilepsy, Alzheimer’s disease, and other neurodegenerative diseases. Currently it is not possible to use this successful tracer in clinics without a cyclotron, because of the short half-life of carbon-11. We developed two new fluorine-18 labeled (R)-verapamil analogs, with the benefit of a longer half-life. The synthesis of (R)-N-[18F]fluoroethylverapamil ([18F]1) and (R)-O-[18F]fluoroethylnorverapamil ([18F]2) has been described. [18F]1 was obtained in reaction of (R)-norverapamil with the volatile [18F]fluoroethyltriflate acquired from bromoethyltosylate and a silver trilate column with a radiochemical yield of 2.7% ± 1.2%. [18F]2 was radiolabeled by direct fluorination of precursor 13 and required final Boc-deprotection with TFA resulting in a radiochemical yield of 17.2% ± 9.9%. Both tracers, [18F]1 and [18F]2, were administered to Wistar rats, and blood plasma and brain samples were analyzed for metabolic stability. Using [18F]1 and [18F]2, PET scans were performed in Wistar rats at baseline and after blocking with tariquidar, showing a 3.6- and 2.4-fold increase in brain uptake in the blocked rats, respectively. In addition, for both [18F]1 and [18F]2, PET scans in Mdr1a/b(−/−), Bcrp1(−/−), and WT mice were acquired, in which [18F]2 showed a more specific brain uptake in Mdr1a/b(−/−) mice and no increased signal in Bcrp1(−/−) mice. [18F]2 was selected as the best performing tracer and should be evaluated further in clinical studies.

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Development of Fluorine-18 Labeled Metabolically Activated Tracers for Imaging of Drug Efflux Transporters with Positron Emission Tomography

Cited by 19 publications

References 58 publications

Ring-Closing Synthesis of Dibenzothiophene Sulfonium Salts and Their Use as Leaving Groups for Aromatic ¹⁸F-Fluorination

Ring-Closing Synthesis of Dibenzothiophene Sulfonium Salts and Their Use as Leaving Groups for Aromatic ¹⁸F-Fluorination

Imaging the Impact of the P-Glycoprotein (ABCB1) Function on the Brain Kinetics of Metoclopramide

Synthesis and Evaluation of New Fluorine-18 Labeled Verapamil Analogs To Investigate the Function of P-Glycoprotein in the Blood–Brain Barrier

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Development of Fluorine-18 Labeled Metabolically Activated Tracers for Imaging of Drug Efflux Transporters with Positron Emission Tomography

Cited by 19 publications

References 58 publications

Ring-Closing Synthesis of Dibenzothiophene Sulfonium Salts and Their Use as Leaving Groups for Aromatic 18F-Fluorination

Ring-Closing Synthesis of Dibenzothiophene Sulfonium Salts and Their Use as Leaving Groups for Aromatic 18F-Fluorination

Imaging the Impact of the P-Glycoprotein (ABCB1) Function on the Brain Kinetics of Metoclopramide

Synthesis and Evaluation of New Fluorine-18 Labeled Verapamil Analogs To Investigate the Function of P-Glycoprotein in the Blood–Brain Barrier

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Ring-Closing Synthesis of Dibenzothiophene Sulfonium Salts and Their Use as Leaving Groups for Aromatic ¹⁸F-Fluorination

Ring-Closing Synthesis of Dibenzothiophene Sulfonium Salts and Their Use as Leaving Groups for Aromatic ¹⁸F-Fluorination