title: Synthesis of spirocyclic sigma1 receptor ligands as potential PET radiotracers, structure-affinity relationships and in vitro metabolic stability.
abstract: Several 3H-spiro[[2]benzofuran-1,4'-piperidines] bearing a p-fluorobenzyl residue at the N-atom and various substituents in position 3 of the benzofuran system were synthesized. The crucial reaction steps are the addition of a lithiated benzaldehyde derivative to the p-fluorobenzylpiperidone 5 and the BF(3).OEt(2) catalyzed substitution of the methoxy group of 2a by various nucleophiles. Structure-affinity relationship studies revealed that compounds with two protons (2d), a methoxy group (2a), and a cyano group (2e) in position 3 possess subnanomolar sigma(1) affinity (K(i)=0.18 nM, 0.79 nM, 0.86 nM) and high selectivity against the sigma(2) subtype. The metabolites of 2a, 2d, and 2e, which were formed upon incubation with rat liver microsomes, were identified. Additionally, the rate of metabolic degradation of 2a, 2d, and 2e was determined and compared with the degradation rate of the non-fluorinated spirocyclic compound 1. For the synthesis of the potential PET tracers [(18)F]2a and [(18)F]2e two different radiosynthetic approaches were followed.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Hittorfstrasse 58-62, D-48149 Münster, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Grosse Maestrup
authors.forename: Christian
authors.initials: C
authors.lastname: Wiese
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Achim
authors.initials: A
authors.lastname: Hiller
authors.forename: Steffen
authors.initials: S
authors.lastname: Fischer
authors.forename: Matthias
authors.initials: M
authors.lastname: Scheunemann
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004355:Drug Stability; D006168:Guinea Pigs; D006801:Humans; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D017480:Receptors, sigma / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
chemical_list: D003577:Cytochrome P-450 Enzyme System; D010880:Piperidines; D019275:Radiopharmaceuticals; D017480:Receptors, sigma; D013141:Spiro Compounds; D000097605:Sigma-1 Receptor; C106107:sigma-2 receptor