title: PET Imaging Evaluation of Four σ1Radiotracers in Nonhuman Primates.
abstract: The σ1receptors (S1Rs) are implicated in a variety of diseases including Alzheimer disease and cancer. Previous PET S1R radiotracers are characterized by slow kinetics or off-target binding that impedes their use in humans. Here, we report the first PET imaging evaluation in rhesus monkeys of 418F-labeled spirocyclic piperidine-based PET radiotracers (18F-1to18F-4).Methods:Baseline scans for the 4 radiotracers were obtained on an adult male rhesus monkey. Blocking scans were obtained with the S1R-selective agonist SA4503 to assess binding specificity of18F-2and18F-4Arterial input functions were measured, and binding parameters were determined with kinetic modeling analysis.Results:In the rhesus brain, all 4 radiotracers showed high and fast uptake. Tissue activity washout was rapid for18F-2and18F-4, and much slower for18F-1and18F-3, in line with their respective in vitro S1R-binding affinities. Both the 1-tissue-compartment and multilinear analysis-1 kinetic models provided good fits of time-activity curves and reliable estimates of distribution volume. Regional distribution volume values were highest in the cingulate cortex and lowest in the thalamus for all radiotracers.18F-4showed greater differential uptake across brain regions and 3-fold-higher binding potential than18F-2SA4503 at the dose of 0.5 mg/kg blocked approximately 85% (18F-2) and 95% (18F-4) of radiotracer binding.Conclusion:Tracers18F-2and18F-4displayed high brain uptake and fast tissue kinetics, with18F-4having higher specific binding signals than18F-2in the same monkey. Taken together, these data indicate that both18F-2and18F-4possess the requisite kinetic and imaging properties as viable PET tracers for imaging S1R in the human brain.
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut.
authors.forename: Evan
authors.initials: E
authors.lastname: Baum
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut.
authors.forename: Zhengxin
authors.initials: Z
authors.lastname: Cai
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut.
authors.forename: Frederic
authors.initials: F
authors.lastname: Bois
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut.
authors.forename: Daniel
authors.initials: D
authors.lastname: Holden
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut.
authors.forename: Shu-Fei
authors.initials: SF
authors.lastname: Lin
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut.
authors.forename: Teresa
authors.initials: T
authors.lastname: Lara-Jaime
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut.
authors.forename: Michael
authors.initials: M
authors.lastname: Kapinos
authors.affiliation: Ministry of Education Key Laboratory of Radiopharmaceuticals, College of Chemistry, Beijing Normal University, Beijing, China.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany; and.
authors.forename: Winnie
authors.initials: W
authors.lastname: Deuther-Conrad
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany; and.
authors.forename: Steffen
authors.initials: S
authors.lastname: Fischer
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany; and.
authors.forename: Sladjana
authors.initials: S
authors.lastname: Dukic-Stefanovic
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Westfälische Wilhelms-Universität Münster, Münster, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Bunse
authors.affiliation: Department of Pharmaceutical and Medicinal Chemistry, Westfälische Wilhelms-Universität Münster, Münster, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Leipzig, Germany; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.affiliation: Ministry of Education Key Laboratory of Radiopharmaceuticals, College of Chemistry, Beijing Normal University, Beijing, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Jia
authors.affiliation: PET Center, Department of Radiology and Biomedical Imaging, Yale University, New Haven, Connecticut henry.huang@yale.edu.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D005462:Fluorine Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D057054:Molecular Imaging / Q000379:methods*; D009928:Organ Specificity / Q000502:physiology; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D017480:Receptors, sigma / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D000097605:Sigma-1 Receptor
chemical_list: D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor
keywords: 18F; PET; radioligand; rhesus monkey; sigma-1 receptor