Evaluation of spirocyclic 3-(3-fluoropropyl)-2-benzofurans as sigma1 receptor ligands for neuroimaging with positron emission tomography.
A series of various N-substituted 3-(3-fluoropropyl)-3H-spiro[[2]benzofuran-1,4'-piperidines] (7) has been synthesized. In receptor binding studies, the N-benzyl derivative 7a (WMS-1813) revealed extraordinarily high sigma(1) receptor affinity (K(i) = 1.4 nM) and excellent sigma(1)/sigma(2) selectivity (>600 fold). In vitro biotransformation of 7a with rat liver microsomes led to three main metabolites. N-Debenzylation was inhibited by introduction of an N-phenylethyl residue (7 g). The PET tracer [(18)F]7a was synthesized by nucleophilic substitution of the tosylate 13 with K[(18)F]F-K222-carbonate complex. The decay corrected radiochemical yield of [(18)F]7a was 35-48% with a radiochemical purity of >99.5% and a specific activity of 150-238 GBq/micromol. The radiotracer properties were evaluated in female CD-1 mice by organ distribution and ex vivo brain autoradiography. The radiotracer uptake in the brain was fast and sufficient, with values of approximately 4% injected dose per gram. Target specificity of [(18)F]7a was validated in blocking studies by preapplication of haloperidol, and significant reduction in the uptake of radioactivity was observed in the brain and peripheral organs expressing sigma(1) receptors.
Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Münster, Germany.
Eva Grosse
EG
Maestrup
Steffen
S
Fischer
Christian
C
Wiese
Dirk
D
Schepmann
Achim
A
Hiller
Winnie
W
Deuther-Conrad
Jörg
J
Steinbach
Bernhard
B
Wünsch
Peter
P
Brust
D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis / Q000378:metabolism; D001711:Biotransformation; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D005260:Female; D005462:Fluorine Radioisotopes; D008024:Ligands; D051379:Mice; D008862:Microsomes, Liver; D009474:Neurons / Q000000981:diagnostic imaging* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis; D051381:Rats; D017480:Receptors, sigma / Q000032:analysis / Q000378:metabolism*; D000097605:Sigma-1 Receptor
D001572:Benzofurans; D005462:Fluorine Radioisotopes; D008024:Ligands; D019275:Radiopharmaceuticals; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor