Synthesis and evaluation of a (18) F-labeled 4-phenylpiperidine-4-carbonitrile radioligand for σ1 receptor imaging.
We report the design and synthesis of several 4-phenylpiperidine-4-carbonitrile derivatives as σ1 receptor ligands. In vitro radioligand competition binding assays showed that all the ligands exhibited low nanomolar affinity for σ1 receptors (Ki (σ1 ) = 1.22-2.14 nM) and extremely high subtype selectivity (Ki (σ2 ) = 830-1710 nM; Ki (σ2 )/Ki (σ1 ) = 680-887). [(18) F]9 was prepared in 42-46% isolated radiochemical yield, with a radiochemical purity of >99% by HPLC analysis after purification, via nucleophilic (18) F(-) substitution of the corresponding tosylate precursor. Biodistribution studies in mice demonstrated high initial brain uptakes and high brain-to-blood ratios. Administration of SA4503 or haloperidol 5 min prior to injection of [(18) F]9 significantly reduced the accumulation of radiotracers in organs known to contain σ1 receptors. Two radioactive metabolites were observed in the brain at 30 min after radiotracer injection. [(18) F]9 may serve as a lead compound to develop suitable radiotracers for σ1 receptor imaging with positron emission tomography.
Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China.
Jiajun
J
Ye
Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China.
Xia
X
Wang
Helmholtz-Zentrum Dresden-Rossendorf, Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, 04318, Leipzig, Germany.
Winnie
W
Deuther-Conrad
Nuclear Medicine Department, Chinese PLA General Hospital, Beijing, 100853, China.
Jinming
J
Zhang
Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China.
Jianzhou
J
Li
Nuclear Medicine Department, Chinese PLA General Hospital, Beijing, 100853, China.
Xiaojun
X
Zhang
Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China.
Liang
L
Wang
Helmholtz-Zentrum Dresden-Rossendorf, Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, 04318, Leipzig, Germany.
Jörg
J
Steinbach
Helmholtz-Zentrum Dresden-Rossendorf, Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, 04318, Leipzig, Germany.
Peter
P
Brust
Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China.
Hongmei
H
Jia
D000818:Animals; D060326:Chemistry Techniques, Synthetic; D004355:Drug Stability; D005462:Fluorine Radioisotopes; D007553:Isotope Labeling; D008024:Ligands; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D017480:Receptors, sigma / Q000378:metabolism*; D014018:Tissue Distribution
C000624967:1-(4-(2-fluoroethoxy)benzyl)-4-phenylpiperidine-4-carbonitrile; D005462:Fluorine Radioisotopes; D008024:Ligands; D010880:Piperidines; D017480:Receptors, sigma
4-phenylpiperidine-4-carbonitrile derivatives; fluorine-18; molecular probe; positron emission tomography; σ1 receptor