title: Pharmacological stress myocardial perfusion imaging with the potent and selective A(2A) adenosine receptor agonists ATL193 and ATL146e administered by either intravenous infusion or bolus injection.
abstract: BACKGROUND
  Adenosine (Ado) and dipyridamole are alternatives to exercise stress for myocardial perfusion imaging. Though generally safe, side effects frequently occur that cause patient discomfort and sometimes lead to premature termination of the study or require aminophylline administration. Recently, a new class of A(2A) Ado receptor agonists was synthesized. ATL193 and ATL146e are 2-propynylcyclohexyl-5'-N-ethylcarboxamido derivatives of Ado. The study goals were to evaluate the potency and selectivity of these new compounds on recombinant canine Ado receptors and to evaluate their hemodynamic properties in dogs to assess their usefulness as vasodilators for myocardial perfusion imaging.
  
  
  RESULTS
  In assays of recombinant canine Ado receptors, ATL-193 and ATL-146e were highly selective for the A(2A) over the A(1) and A(3) receptors and were more potent than MRE-0470 and CGS-21680. In 16 anesthetized dogs, the agonists were administered by infusion (ATL-193; n=7 normal) or bolus injection (ATL-146e; n=9 critical left anterior descending coronary artery stenosis), and hemodynamic responses were compared with those of Ado. Both agonists produced dose-dependent coronary flow (CF) elevation without provoking the hypotension observed with Ado. After an ATL-146e bolus, the CF increase was sustained for several minutes, providing ample time for injection and myocardial uptake of (99m)Tc-sestamibi, and CF returned to baseline within 20 minutes. The CF increase was completely blocked by the selective A(2A) antagonist ZM241385 (3 microgram. kg(-1). min(-1)).
  
  
  CONCLUSIONS
  ATL-193 and ATL-146e are highly potent and selective Ado A(2A) receptor agonists with excellent potential for use as vasodilators for myocardial perfusion imaging. An important advantage of ATL-146e is the ability to administer it by bolus injection.
authors.affiliation: Experimental Cardiology Laboratory, Cardiovascular Division, Department of Internal Medicine, University of Virginia Health System, Charlottesville, USA. dglover@virginia.edu
authors.forename: D K
authors.initials: DK
authors.lastname: Glover
authors.forename: M
authors.initials: M
authors.lastname: Ruiz
authors.forename: K
authors.initials: K
authors.lastname: Takehana
authors.forename: F D
authors.initials: FD
authors.lastname: Petruzella
authors.forename: L M
authors.initials: LM
authors.lastname: Riou
authors.forename: J M
authors.initials: JM
authors.lastname: Rieger
authors.forename: T L
authors.initials: TL
authors.lastname: Macdonald
authors.forename: D D
authors.initials: DD
authors.lastname: Watson
authors.forename: J
authors.initials: J
authors.lastname: Linden
authors.forename: G A
authors.initials: GA
authors.lastname: Beller
mesh_terms: D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D003327:Coronary Disease / Q000000981:diagnostic imaging / Q000503:physiopathology; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D009206:Myocardium / Q000378:metabolism; D058906:Purinergic P1 Receptor Agonists; D011687:Purines / Q000494:pharmacology*; D011869:Radioligand Assay; D011877:Radionuclide Imaging; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D017256:Technetium Tc 99m Sestamibi
chemical_list: C431129:ATL 146e; D003509:Cyclohexanecarboxylic Acids; D058906:Purinergic P1 Receptor Agonists; D011687:Purines; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; D011994:Recombinant Proteins; D017256:Technetium Tc 99m Sestamibi; D000241:Adenosine