N-(3-lodoprop-2E-enyl)-2beta-carbomethoxy-3beta-(3',4'-dichloro phenyl)nortropane (beta-CDIT), a tropane derivative: pharmacological characterization as a specific ligand for the dopamine transporter in the rodent brain.
N-(3-Iodoprop-2E-enyl)-2beta-carbomethoxy-3beta-(3',4'-dichl orophenyl)nortropane (beta-CDIT), a new iodinated tropane derivative, has been synthesized and radiolabeled with iodine. [125I]beta-CDIT was tested in vitro and ex vivo as a probe for the dopamine transporter site in the rat brain, and behavioral studies were performed in mice. Saturation studies in the striatum revealed that [125I]beta-CDIT bound to a single high-affinity site. The Kd value was 0.18 +/- 0.07 nM, and the corresponding Bmax value was 500 +/- 80 fmol/mg of protein. The pharmacological profile of specific [125I]beta-CDIT binding in the striatum was consistent with that of the dopamine transporter. In addition, competition studies in cerebral cortex regions with [3H]paroxetine and [3H]nisoxetine showed a very low affinity of beta-CDIT for the 5-hydroxytryptamine (Ki = 50 nM) and norepinephrine (Ki = 500 nM) transporters compared with beta-CIT (corresponding Ki values were 3 and 80 nM). In contrast, the competition of beta-CDIT with [3H]GBR 12935 in the striatal region (Ki = 29 nM) was of the same order of value as for beta-CIT (Ki = 27.5 nM). Behavioral experiments in mice showed that both beta-CDIT and beta-CIT induced stimulation of locomotor activity. Ex vivo autoradiographic studies in rats using [125I]beta-CDIT demonstrated high densities of [125I]beta-CDIT binding sites in areas known to be rich in dopaminergic innervation. Because of its high affinity and high selectivity for the dopamine transporter, [125I]beta-CDIT should be a valuable ligand for the exploration of the dopamine transporter with single-photon emission computed tomography.
Garreau
L
L
INSERM U316, Laboratoire de Biophysique Médicale et Pharmaceutique, Tours, France.
Emond
P
P
Belzung
C
C
Guilloteau
D
D
Frangin
Y
Y
Besnard
J C
JC
Chalon
S
S
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins; D009662:Nortropanes / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015899:Tomography, Emission-Computed, Single-Photon
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C107080:N-(3-iodoprop-2-enyl)-2-carbomethoxy-3-(3',4'-dichlorophenyl)nortropane; D009419:Nerve Tissue Proteins; D009662:Nortropanes; D004298:Dopamine