title: Cardiac retention of PET neuronal imaging agent LMI1195 in different species: impact of norepinephrine uptake-1 and -2 transporters.
abstract: BACKGROUND
  Released sympathetic neurotransmitter norepinephrine (NE) in the heart is cleared by neuronal uptake-1 and extraneuronal uptake-2 transporters. Cardiac uptake-1 and -2 expression varies among species, but the uptake-1 is the primary transporter in humans. LMI1195 is an NE analog labeled with (18)F for PET evaluation of cardiac neuronal function. This study investigated the impact of cardiac neuronal uptake-1 associated with different species on LMI1195 heart uptake.
  
  
  METHODS
  Cardiac uptake-1 was blocked by desipramine, a selective uptake-1 inhibitor, and sympathetic neuronal denervation was induced by 6-hydroxydopamine, a neurotoxin, in rats, rabbits and nonhuman primates (NHP). Tissue biodistribution and cardiac imaging of LMI1195 and (123)I-metaiodobenzylguanidine (MIBG) were performed.
  
  
  RESULTS
  In rats, uptake-1 blockade did not alter LMI1195 heart uptake compared to the control at 60-min post injection [1.41 ± 0.07 vs. 1.47 ± 0.23 % injected dose per gram tissue (%ID/g)]. In contrast, LMI1195 heart uptake was reduced by 80% in uptake-1 blocked rabbits. In sympathetically denervated rats, LMI1195 heart uptake was similar to the control (2.18 ± 0.40 vs. 2.58 ± 0.76 %ID/g). However, the uptake decreased by 79% in denervated rabbits. Similar results were found in MIBG heart uptake in rats and rabbits with uptake-1 blockade. Consistently, LMI1195 cardiac imaging showed comparable myocardial activity in uptake-1 blocked or sympathetically denervated rats to the control, but marked activity reduction in uptake-1 blocked or denervated rabbits and NHPs.
  
  
  CONCLUSIONS
  LMI1195 is retained in the heart of rabbits and NHPs primarily via the neuronal uptake-1 with high selectivity and can be used for evaluation of cardiac sympathetic denervation. Similar to the human, the neuronal uptake-1 is the dominant transporter for cardiac retention of NE analogs in rabbits and NHPs, but not in rats.
authors.affiliation: Discovery Research, Lantheus Medical Imaging, 331 Treble Cove Rd, N Billerica, MA 01826, 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: Mikhail
authors.initials: M
authors.lastname: Kagan
authors.forename: Mary
authors.initials: M
authors.lastname: Guaraldi
authors.forename: Paula
authors.initials: P
authors.lastname: Silva
authors.forename: Michael
authors.initials: M
authors.lastname: Azure
authors.forename: David
authors.initials: D
authors.lastname: Onthank
authors.forename: Simon P
authors.initials: SP
authors.lastname: Robinson
mesh_terms: D019797:3-Iodobenzylguanidine / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003714:Denervation; D003891:Desipramine / Q000494:pharmacology; D005464:Fluorobenzenes / Q000378:metabolism*; D006146:Guanidines / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D009206:Myocardium / Q000378:metabolism*; D009474:Neurons / Q000000981:diagnostic imaging* / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011817:Rabbits; D051381:Rats; D013045:Species Specificity; D013564:Sympathetic Nervous System / Q000166:cytology
chemical_list: D005464:Fluorobenzenes; D006146:Guanidines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D019797:3-Iodobenzylguanidine; D003891:Desipramine; C561360:flubrobenguane