title: Characterization of FlipIDAM as a SERT-selective SPECT imaging agent.
abstract: BACKGROUND
  Biological evaluation of ([(125)I]4), a new single-photon emission computed tomography (SPECT) radioligand for imaging the serotonin transporter (SERT) which displayed improved in vivo kinetics for mapping SERT binding sites in the brain.
  
  
  METHODS
  In vitro binding studies of [(125)I]4 were performed with membrane homogenates of LLC-PK1 cells stably transfected and overexpressing one of the monoamine transporter (SERT, DAT or NET) and rat cortical homogenates. Biodistribution and ex vivo autoradiography studies were carried out in rats. In vivo competition experiments were evaluated to determine the SERT selectivity of [(125)I]4 vs. ([(125)I]1).
  
  
  RESULTS
  In vitro binding studies of 4 showed excellent binding affinity (Ki,SERT=0.90 ± 0.05 nM) and excellent selectivity over the other monoamine transporters (100 fold and >4000 fold for NET and DAT respectively). Scatchard analysis of saturation binding of [(125)I]4 to rat cortical homogenates gave a Kd value of 0.5 ± 0.09 nM and a Bmax value of 801.4 ± 58.08 fmol/mg protein. The biodistribution study showed rapid high brain uptake (3.09 ± 0.11% dose/organ at 2 min) and a good target to non-target ratio (hypothalamus to cerebellum) at 30 min (2.62) compared to [(125)I]1 (2.19). Ex vivo autoradiography showed that FlipIDAM localizes in accordance with SERT distribution patterns in the brain. In vivo and ex vivo competition experiments with specific and non-specific SERT compounds also showed that [(125)I]4 binds specifically to SERT rich regions.
  
  
  CONCLUSIONS
  The biological evaluation of [(125)I]4 demonstrates that [(123)I]4 would be a good candidate for SPECT imaging of SERT.
authors.affiliation: Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Lemoine
authors.forename: Brian P
authors.initials: BP
authors.lastname: Lieberman
authors.forename: Karl
authors.initials: K
authors.lastname: Ploessl
authors.forename: Pinguan
authors.initials: P
authors.lastname: Zheng
authors.forename: Hank F
authors.initials: HF
authors.lastname: Kung
mesh_terms: D000818:Animals; D001345:Autoradiography; D001596:Benzylamines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002460:Cell Line; D007553:Isotope Labeling; D008024:Ligands; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D013379:Substrate Specificity; D013440:Sulfides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: C581853:(2-((2-((dimethylamino)methyl)-4-iodophenyl)thio)phenyl)methanol; D001596:Benzylamines; D008024:Ligands; D050486:Serotonin Plasma Membrane Transport Proteins; D013440:Sulfides
keywords: (+)-McN5652; (2-((2-((dimethylamino)methyl)-4-iodophenyl)thio)phenyl)methanol); (5-iodo-2-((2-((dimethylamino)methyl)phenyl)thio)benzyl alcohol); (N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine); 2-((2-((dimethylamino)methyl)-phenyl)thio)-5-iodophenylamine; 2-(2'-((dimethylamino)methyl)-4'-iodophenylthio)benzenamine; 2<beta>-carbomethoxy-3<beta>-(4-iodophenyl); 2<beta>-carbomethoxy-3<beta>-(4-iodophenyl)tropane; 5-HT; 5-HTT; <beta>-CIT; ADAM (2); Brain imaging; DASB; FlipADAM (3); FlipIDAM (4); IACUC; IDAM (1); Institutional Animal Care and Use Committee; MADAM; N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine; Radioligand; SERT; SPECT; SSRI; St; Th; nor-<beta>-CIT; selective serotonin reuptake inhibitor; serotonin; serotonin transporter; single photon emission computed tomography; striatum; thalamus; trans-1,2,3,5,6,10-<beta>-hexahydro-6-[4-(methylthio)phenyl-[pyrrolo-[2,1-<alpha>]isoquinoline