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

Abstract

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.

• Authors: Renske M Raaphorst, Gert Luurtsema, Robert C Schuit, Esther J M Kooijman, Philip H Elsinga, Adriaan A Lammertsma, Albert D Windhorst
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 8 Issue 9 Pg. 1925-1936 (09 20 2017) ISSN: 1948-7193 [Electronic] United States
• PMID: 28650628 (Publication Type: Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• Abcg2 protein, mouse
• Central Nervous System Agents
• Quinolines
• Radiopharmaceuticals
• multidrug resistance protein 3
• Verapamil
• tariquidar

Topics

• ATP Binding Cassette Transporter, Subfamily B (deficiency, genetics)
• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2 (deficiency, genetics)
• Animals
• Blood-Brain Barrier (metabolism)
• Central Nervous System Agents (pharmacology)
• Drug Evaluation, Preclinical
• Drug Stability
• Male
• Mice, Knockout
• Molecular Structure
• Positron-Emission Tomography
• Quinolines (pharmacology)
• Radiopharmaceuticals (chemical synthesis, pharmacokinetics)
• Rats, Wistar
• Tissue Distribution
• Verapamil (chemical synthesis, pharmacology)
• ATP-Binding Cassette Sub-Family B Member 4