title: Design and synthesis of new agents for neuronal nicotinic acetylcholine receptor (nAChRs) imaging.
abstract: BACKGROUND
  The most abundant subtype of cerebral nicotinic acetylcholine receptors (nAChR), α4β2, plays a critical role in various brain functions and pathological states. Due to rapid technological progress in chemistry, bioinformatics, structural biology and computer technology, computer aided drug design (CADD) plays a more and more important role in today's drug discovery.
  
  
  METHODS
  Two novel 3-pyridyl ether nicotinic ligands-3-((pyridine-2-yl)methoxy)-5-iodopyridine, and 3-(((S)-pyrrolidin-2-yl)methoxy)-5-((4-iodobenzyloxy)-methyl)pyridine were designed and synthesized and radiolabeled with I-125 based on our 3D-QSAR models reported previously. Their ability to label high-affinity brain nicotinic acetylcholine receptors (nAChRs) was evaluated.
  
  
  RESULTS
  [¹²⁵I]3-((pyridin-2-yl)methoxy)-5-iodopyridine shows rapid accumulation and elimination with peak (1.86%ID/g) at 5 min post injection, but has high blood uptake. [¹²⁵I]3-(((S)-pyrrolidin-2-yl)methoxy)-5-((4-iodobenzyloxy)methyl)pyridine entered the brain with maximal uptake value 3.01%ID/g at 15 min after injection, and showed approximately 27% inhibition of radioactivity uptake in thalamus in mice pretreated with nicotine.
  
  
  CONCLUSIONS
  The results of this preliminary study show that [¹²⁵I]3-(((S)-pyrrolidin-2-yl)methoxy)-5-((4-iodobenzyloxy)methyl)pyridine shows relatively high uptake to the brain, however, since the in vivo selectivity for α4β2 nAChRs was not enough, [¹²⁵I]3-(((S)-pyrrolidin-2-yl)methoxy)-5-((4-iodobenzyloxy)methyl)pyridine does not have the required properties for imaging nAChRs using SPECT. Structure optimization is needed for specific visualization of brain α4β2 nAChRs in vivo.
authors.affiliation: Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, PR China.
authors.forename: Yongjuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Haijing
authors.initials: H
authors.lastname: Yu
authors.forename: Lingzhou
authors.initials: L
authors.lastname: Zhao
authors.forename: Huabei
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D057927:Hydrophobic and Hydrophilic Interactions; D007457:Iodine Radioisotopes; D051379:Mice; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism*; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: D007457:Iodine Radioisotopes; D011725:Pyridines; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; C403531:nicotinic receptor alpha4beta2