title: LMI1195 PET imaging in evaluation of regional cardiac sympathetic denervation and its potential role in antiarrhythmic drug treatment.
abstract: OBJECTIVE
  Regional cardiac sympathetic denervation (RCSD) associated with reduced noradrenaline transporter (NAT) function has been linked to cardiac arrhythmia. This study examined the association of LMI1195, an (18)F-labeled NAT substrate developed for positron emission tomography (PET) imaging, with NAT in vitro, and its imaging to detect RCSD and guide antiarrhythmic drug treatment in vivo.
  
  
  METHODS
  LMI1195 association with NAT was assessed in comparison with other substrates, noradrenaline (NA) and (123)I-metaiodobenzylguanidine (MIBG), in NAT-expressing cells. LMI1195 cardiac imaging was performed for evaluation of RCSD in a rabbit model surgically developed by regional phenol application on the left ventricular (LV) wall. The normal LV areas in images were quantified as regions with radioactivity ≥50 % maximum. Potential impact of RCSD on dofetilide, an antiarrhythmic drug, induced ECG changes was assessed.
  
  
  RESULTS
  NAT blockade with desipramine reduced LMI1195 cell uptake by 90 ± 3 %, similar to NA and MIBG. NA, MIBG, or self inhibited LMI1195 cell uptake concentration-dependently with comparable IC(50) values (1.09, 0.21, and 0.90 μM). LMI1195 cardiac imaging differentiated innervated and denervated areas in RCSD rabbits. The surgery resulted in a large denervated LV area at 2 weeks which was partially recovered at 12 weeks. Myocardial perfusion imaging with flurpiridaz F 18 showed normal perfusion in RCSD areas. Dofetilide induced more prominent QTc prolongation in RCSD than control animals. However, changes in heart rate were comparable.
  
  
  CONCLUSIONS
  LMI1195 exhibits high association with NAT and can be used for imaging RCSD. The detected RCSD increases cardiac risks to the antiarrhythmic drug, dofetilide, by inducing more QTc prolongation.
authors.affiliation: Discovery Research, Lantheus Medical Imaging, N. Billerica, MA 01862, USA. ming.yu@lantheus.com
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.forename: Jody
authors.initials: J
authors.lastname: Bozek
authors.forename: Melanie
authors.initials: M
authors.lastname: Lamoy
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kagan
authors.forename: Pedro
authors.initials: P
authors.lastname: Benites
authors.forename: David
authors.initials: D
authors.lastname: Onthank
authors.forename: Simon P
authors.initials: SP
authors.lastname: Robinson
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000000981:diagnostic imaging* / Q000188:drug therapy; D001340:Autonomic Nerve Block; D045744:Cell Line, Tumor; D005464:Fluorobenzenes; D006146:Guanidines; D006321:Heart / Q000000981:diagnostic imaging*; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000294:innervation; D006801:Humans; D010627:Phenethylamines / Q000627:therapeutic use; D019800:Phenol; D049268:Positron-Emission Tomography; D011817:Rabbits; D019275:Radiopharmaceuticals; D013449:Sulfonamides / Q000627:therapeutic use
chemical_list: D000889:Anti-Arrhythmia Agents; D005464:Fluorobenzenes; D006146:Guanidines; D010627:Phenethylamines; D019275:Radiopharmaceuticals; D013449:Sulfonamides; D019800:Phenol; C063533:dofetilide; C561360:flubrobenguane