Synthesis, radiolabeling and preliminary in vivo evaluation of [ 18F]FE-PE2I, a new probe for the dopamine transporter

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 16; pp. 4843 - 4845
• Main Authors: Schou, Magnus, Steiger, Carsten, Varrone, Andrea, Guilloteau, Denis, Halldin, Christer
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.08.2009; Elsevier
• Subjects: Animals; Biological and medical sciences; Brain - metabolism; Contrast media. Radiopharmaceuticals; Dopamine Plasma Membrane Transport Proteins - antagonists & inhibitors; Dopamine Plasma Membrane Transport Proteins - metabolism; Dopamine transporter; Fluorine Radioisotopes - chemistry; Haplorhini; Humans; Isotope Labeling; Kinetics; Medical sciences; Nortropanes - chemical synthesis; Nortropanes - chemistry; Nortropanes - pharmacology; PE2I; PET; Pharmacology. Drug treatments; Positron-Emission Tomography; Radioligand; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacology; Rats; Tropane; Dopamine transporter; PE2I; Radioligand; Tropane; PET; Fluorine 18; Ligand; Monkey; Central nervous system; Tissue; Membrane transport; Primates; Chemical synthesis; Dopamine; Fluorine Isotopes; Radiolabelling; Rodentia; Catecholamine; In vivo; Vertebrata; Mammalia; Animal; Biogenic amine; Distribution; Neurotransmitter
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.06.032

The synthesis, radiosynthesis and preliminary PET evaluation of [18F]6 ( K i = 17 nM) is reported. A new dopamine transporter (DAT) ligand, ( E)- N-(3-iodoprop-2-enyl)-2β-carbofluoroethoxy-3β-(4′-methyl-phenyl) nortropane (FE-PE2I, 6), derived from PE2I ( 1), was prepared and found to be a potent inhibitor of rodent DAT in vitro. Compound 6 was radiolabelled with fluorine-18 ( t 1/2 = 109.8 min) for PET studies in monkeys. In vivo PET measurements showed a regional distribution in brain that corresponds to the known distribution of DAT. This binding was specific, reversible and the kinetics of [ 18F] 6 binding in brain were faster than for its lead compound, [ 11C] 1. The possible presence of a hydroxymethyl-radiometabolite formed by oxidation in the 3β-benzylic position of [ 18F] 6 warrants further detailed evaluation of the metabolism of [ 18F] 6. [ 18F] 6 is a potential radioligand for imaging DATs in the human brain with PET.