ACS Chem Neurosci. 2018 Jun 20;9(6):1283-1289. doi: 10.1021/acschemneuro.8b00096.

New Dopamine D2 Receptor Agonist, [3H]MCL-536, for Detecting Dopamine D2high Receptors in Vivo.

Subburaju S1,2, Sromek AW1,2, Seeman P3, Neumeyer JL1,2.
1 Division of Basic Neuroscience, Medicinal Chemistry Laboratory , McLean Hospital , Belmont , Massachusetts 02478 , United States.
2 Department of Psychiatry , Harvard Medical School , Boston , Massachusetts 02115 , United States.
3 Departments of Pharmacology and Psychiatry , University of Toronto , 260 Heath St. West, unit 605 , Toronto , Ontario Canada M5P 3L6.

Abstract

Increases in the D2 receptor high affinity state are associated with certain neurological disorders. We synthesized and characterized the high-affinity D2high ligand [3H]MCL-536 in competition binding against the D2/3 agonist R-(-)- N- n-propylnorapomorphine (NPA) and the D2/3 antagonist raclopride. The total binding of [3H]MCL-536 (minus that in the presence of 100 nM NPA) was measured by saturation binding in CHO cells expressing human D2long; the data yielded separable, nonsaturable nonspecific, and saturable specific components. The former represents an aporphine site common to NPA and [3H]MCL-536. The latter indicated specific binding to the total D2 receptors (both high and low-affinity states). [3H]MCL-536 had a Kd of 0.8 nM. In competition binding, NPA had a Ki of 0.16 nM, and raclopride had a Ki of 0.9 nM. Co-incubation with guanylylimidodiphosphate abolished binding to D2high. This unique profile makes radiolabeled MCL-536 a versatile tool for diagnostics and therapeutics, and may quantify D2high sites in schizophrenia and PD patients in vivo.

KEYWORDS:

Dopamine D2high receptor; PET; Parkinson’s disease; aporphine; schizophrenia; tritiated radioligand

PMID: 29641175

 

Supplement:

[3H]MCL-536 is a high affinity, the dopamine D2 receptor selective radioligand. Because it is an agonist, it is highly sensitive to changes of the D2 receptor into its high affinity state. This is a useful property for probing the status of the dopaminergic system, especially in relation to different neurological disorders which involve the dopaminergic system, eg., Parkinson’s disease, Huntington’s disease, or schizophrenia. [3H]MCL-536 is primarily intended for receptor binding assays. It can be used to measure the dopaminergic response in vitro or ex vivo to medications being developed for these disorders, thereby facilitating the drug discovery process.