Characterization of [3H]LS-3-134, a novel arylamide phenylpiperazine D3 dopamine receptor selective radioligand

Authors

  • Claudia Rangel-Barajas,

    1. Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, USA
    Search for more papers by this author
  • Maninder Malik,

    1. Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, USA
    Search for more papers by this author
  • Michelle Taylor,

    1. Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, USA
    Search for more papers by this author
  • Kim A. Neve,

    1. Research Service, Department of Veterans Affairs Medical Center, Portland, Oregon, USA
    Search for more papers by this author
  • Robert H. Mach,

    1. Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
    Search for more papers by this author
  • Robert R. Luedtke

    Corresponding author
    1. Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, USA
    • Address correspondence and reprint requests to Robert R. Luedtke, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA. E-mail: robert.luedtke@unthsc.edu

    Search for more papers by this author

Abstract

LS-3-134 is a substituted N-phenylpiperazine derivative that has been reported to exhibit: (i) high-affinity binding (Ki value 0.2 nM) at human D3 dopamine receptors, (ii) > 100-fold D3 versus D2 dopamine receptor subtype binding selectivity, and (iii) low-affinity binding (Ki > 5000 nM) at sigma 1 and sigma 2 receptors. Based upon a forskolin-dependent activation of the adenylyl cyclase inhibition assay, LS-3-134 is a weak partial agonist at both D2 and D3 dopamine receptor subtypes (29% and 35% of full agonist activity, respectively). In this study, [3H]-labeled LS-3-134 was prepared and evaluated to further characterize its use as a D3 dopamine receptor selective radioligand. Kinetic and equilibrium radioligand binding studies were performed. This radioligand rapidly reaches equilibrium (10–15 min at 37°C) and binds with high affinity to both human (Kd = 0.06 ± 0.01 nM) and rat (Kd = 0.2 ± 0.02 nM) D3 receptors expressed in HEK293 cells. Direct and competitive radioligand binding studies using rat caudate and nucleus accumbens tissue indicate that [3H]LS-3-134 selectively binds a homogeneous population of binding sites with a dopamine D3 receptor pharmacological profile. Based upon these studies, we propose that [3H]LS-3-134 represents a novel D3 dopamine receptor selective radioligand that can be used for studying the expression and regulation of the D3 dopamine receptor subtype.

Ancillary