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Synthesis and Preclinical Evaluation of Three Novel Fluorine-18 Labeled Radiopharmaceuticals for P-Glycoprotein PET Imaging at the Blood–Brain Barrier

Savolainen, H., Cantore, M., Colabufo, N. A., Elsinga, P. H., Windhorst, A. D. & Luurtsema, G., Jul-2015, In : Molecular pharmaceutics. 12, 7, p. 2265-2275 11 p.

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  • Synthesis and Preclinical Evaluation of Three Novel Fluorine-18 Labeled Radiopharmaceuticals for P-Glycoprotein PET Imaging at the Blood–Brain Barrier

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DOI

P-Glycoprotein (P-gp), along with other transporter proteins at the blood brain barrier (BBB), limits the entry of many pharmaceuticals into the brain. Altered P-gp function has been found in several neurological diseases. To study the P-gp function, many positron emission tomography (PET) radiopharmaceuticals have been developed. Most P-gp radiopharmaceuticals are labeled with carbon-11, while labeling with fluorine-18 would increase their applicability due to longer half-life. Here we present the synthesis and in vivo evaluation of three novel fluorine-18 labeled radiopharmaceuticals: 4-((6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-2-(4-fluorophenyl)oxazole (1a), 2-biphenyl-4-yl-2-fluoroethoxy-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline (2), and 5-(1-(2-fluoroethoxy))-[3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-5,6,7,8-tetrahydronaphthalen (3). Compounds were characterized as P-gp substrates in vitro, and Mdr1a/b((-/-))Bcrp1((-/-)) and wild-type mice were used to assess the substrate potential in vivo. Comparison was made to (R)-[C-11]verapamil, which is currently the most frequently used P-gp substrate. Compound [F-18]3 was performing the best out of the new radiopharmaceuticals; it had 2-fold higher brain uptake in the Mdr1a/b((-/-))Bcrp1((-/-)) mice compared to wild-type and was metabolically quite stable. In the plasma, 69% of the parent compound was intact after 45 min and 96% in the brain. Selectivity of [F-18]3 to P-gp was tested by comparing the uptake in Mdr1a/b((-/-)) mice to uptake in Mdr1a/b((-/-))Bcrp1((-/-)) mice, which was statistically not significantly different. Hence, [F-18]3 was found to be selective for P-gp and is a promising new radiopharmaceutical for P-gp PET imaging at the BBB.

Original languageEnglish
Pages (from-to)2265-2275
Number of pages11
JournalMolecular pharmaceutics
Volume12
Issue number7
Publication statusPublished - Jul-2015

    Keywords

  • blood-brain barrier, P-glycoprotein, BCRP, PET, F-18, radiopharmaceutical, POSITRON-EMISSION-TOMOGRAPHY, CANCER RESISTANCE PROTEIN, IN-VIVO EVALUATION, TRANSPORTERS, DERIVATIVES, TARIQUIDAR, INHIBITORS, DISEASE, MODULATORS

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