Synthesis of a [6-pyridinyl-18F]-labelled fluoro derivative of WAY-100635 as a candidate radioligand for brain 5-HT1A receptor imaging with PET

• Published in: Bioorganic & medicinal chemistry Vol. 11; no. 13; pp. 2769 - 2782
• Main Authors: KARRAMKAM, Mylène, HINNEN, Francoise, BERREHOUMA, Myriam, HLAVACEK, Christophe, VAUFREY, Francoise, HALLDIN, Christer, MCCARRON, Julie A, PIKE, Victor W, DOLLE, Frédéric
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science 03.07.2003
• Subjects: Biological and medical sciences; Brain Chemistry; Contrast media. Radiopharmaceuticals; Fluorine Radioisotopes; Hot Temperature; Isotope Labeling; Ligands; Magnetic Resonance Spectroscopy; Medical sciences; Medicin och hälsovetenskap; Microwaves; Pharmacology. Drug treatments; Piperazines - chemical synthesis; Pyridines - chemical synthesis; Radiopharmaceuticals - chemical synthesis; Receptor, Serotonin, 5-HT1A - analysis; Serotonin Antagonists - chemical synthesis; Tomography, Emission-Computed; Fluorine Isotopes; 5-HT1A Serotonine receptor; Fluorine 18; Radiolabelling; Aminoamide; Nitrogen heterocycle; Ligand; Scintigraphic agent; Carboxamide; Benzenic compound; Chemical synthesis; Monocyclic compound
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(03)00225-6

In recent years, considerable effort has been spent on the design, synthesis and pharmacological characterization of radiofluorinated derivatives of the 5-HT(1A) receptor antagonist, WAY-100635, for the in vivo study of these receptors in human brain with PET. (Pyridinyl-6)-fluoro- and (pyridinyl-5)-fluoro-analogues of WAY-100635 (6-fluoro and 5-fluoro-WAY-100635, 5a/6a) were synthesized as well as the corresponding chloro-, bromo- and nitro-derivatives as precursors for labelling (5b-d and 6b-d). Comparative radiolabelling of these precursors with fluorine-18 (positron-emitting isotope, 109.8 min half-life) clearly demonstrated that only ortho-fluorination in this pyridine series, and not meta-fluorination, is of interest for the preparation of a radioligand by nucleophilic heteroaromatic substitution. 6-[(18)F]Fluoro-WAY-100635 ([(18)F]5a) can be efficiently synthesized in one step, either from the corresponding 6-bromo precursor (using conventional heating at 145 degrees C for 10 min) or from the corresponding 6-nitro precursor (using microwave activation at 100 W for 1 min). Typically, 15-25 mCi (0.55-0.92 GBq) of 6-[(18)F]fluoro-WAY-100635 ([(18)F]5a, 1-2 Ci/micromol or 37-72 GBq/micromol) were obtained in 50-70 min starting from a 100 mCi (3.7 GBq) aliquot of a batch of cyclotron-produced [(18)F]fluoride. This (18)F-labelled radioligand is now being evaluated in PET studies.