title: Evaluation of σ-1 receptor radioligand 18F-FTC-146 in rats and squirrel monkeys using PET.
abstract: The noninvasive imaging of σ-1 receptors (S1Rs) could provide insight into their role in different diseases and lead to novel diagnostic/treatment strategies. The main objective of this study was to assess the S1R radiotracer (18)F-FTC-146 in rats. Preliminary squirrel monkey imaging and human serum/liver microsome studies were performed to gain information about the potential of (18)F-FTC-146 for eventual clinical translation.
  
  
  METHODS
  The distribution and stability of (18)F-FTC-146 in rats were assessed via PET/CT, autoradiography, γ counting, and high-performance liquid chromatography (HPLC). Preliminary PET/MRI of squirrel monkey brain was conducted along with HPLC assessment of (18)F-FTC-146 stability in monkey plasma and human serum.
  
  
  RESULTS
  Biodistribution studies showed that (18)F-FTC-146 accumulated in S1R-rich rat organs, including the lungs, pancreas, spleen, and brain. Pretreatment with known S1R compounds, haloperidol, or BD1047, before radioligand administration, significantly attenuated (18)F-FTC-146 accumulation in all rat brain regions by approximately 85% (P < 0.001), suggesting radiotracer specificity for S1Rs. Similarly, PET/CT and autoradiography results demonstrated accumulation of (18)F-FTC-146 in rat brain regions known to contain S1Rs and that this uptake could be blocked by BD1047 pretreatment. Ex vivo analysis of (18)F-FTC-146 in the brain showed that only intact radiotracer was present at 15, 30, and 60 min, whereas rapid metabolism of residual (18)F-FTC-146 was observed in rat plasma. Preliminary monkey PET/MRI studies demonstrated specific accumulation of (18)F-FTC-146 in the brain (mainly in cortical structures, cerebellum, and vermis) that could be attenuated by pretreatment with haloperidol. HPLC of monkey plasma suggested radioligand metabolism, whereas (18)F-FTC-146 appeared to be stable in human serum. Finally, liver microsome studies revealed that (18)F-FTC-146 has a longer half-life in human microsomes, compared with rodents.
  
  
  CONCLUSIONS
  Together, these results indicate that (18)F-FTC-146 is a promising tool for visualizing S1Rs in preclinical studies and that it has potential for mapping these sites in the human brain.
authors: Molecular Imaging Program at Stanford (MIPS) Department of Radiology, Stanford University, Stanford, California.
authors: Michelle L
authors: ML
authors: James
authors: Bin
authors: B
authors: Shen
authors: Carsten H
authors: CH
authors: Nielsen
authors: Deepak
authors: D
authors: Behera
authors: Christine L
authors: CL
authors: Buckmaster
authors: Christophe
authors: C
authors: Mesangeau
authors: Cristina
authors: C
authors: Zavaleta
authors: Pradeep K
authors: PK
authors: Vuppala
authors: Seshulatha
authors: S
authors: Jamalapuram
authors: Bonnie A
authors: BA
authors: Avery
authors: David M
authors: DM
authors: Lyons
authors: Christopher R
authors: CR
authors: McCurdy
authors: Sandip
authors: S
authors: Biswal
authors: Sanjiv S
authors: SS
authors: Gambhir
authors: Frederick T
authors: FT
authors: Chin
mesh_terms: D000818:Animals; D001381:Azepines / Q000737:chemistry*; D052160:Benzothiazoles / Q000737:chemistry*; D001921:Brain / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008024:Ligands; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D049268:Positron-Emission Tomography; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017480:Receptors, sigma / Q000737:chemistry*; D012453:Saimiri; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed; D000097605:Sigma-1 Receptor
chemical_list: D001381:Azepines; D052160:Benzothiazoles; D008024:Ligands; D019275:Radiopharmaceuticals; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C577112:6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo(d)thiazol-2(3H)-one
keywords: 18F; PET; σ-1 receptor