(S)-N-[(1-Ethyl-2-pyrrolidinyl)methyl]-5-[125I]iodo-2-methoxybenzamide hydrochloride, a new selective radioligand for dopamine D-2 receptors

Abstract

From salicyclic acid, the two enantiomers of N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2-methoxybenzamide (6b) were prepared in a five-step synthesis. With use of Heindel's triazene method for introduction of the radionuclide, the iodine-125-labeled substituted benzamide was obtained with a calculated specific activity of 136 Ci/mmol and 14% radiochemical yield. For the preparation of the iodine-125-labeled benzamide with higher specific activity, this method was unsuccessful and utilization of the corresponding tri-n-butyltin derivative was required. Treatment of the latter in dilute hydrochloric acid with sodium iodide-125 and chloramine-T gave [125I](S)-6b in 56% radiochemical yield and at least 97% radiochemical purity. The displacement of [125I](S)-6b and [3H](S)-sulpiride from their respective binding sites in striatal rat brain homogenates using various neuroleptic agents showed that (S)-6b has the same binding profile but more potent binding for dopamine D-2 receptors than has sulpiride. These experiments also indicate that the S enantiomer of 6b is a specific ligand (KD = 1.2 nM) for the D-2 receptor. Further, the octanol-water partition coefficient of (S)-6b as determined by reverse-phase high-performance liquid chromatography was found to be 40 times greater than that for sulpiride. Thus (S)-6b has a lipophilicity that will allow a relatively higher uptake into the brain compared to sulpiride. In vivo experiments with rats show that [125I](S)-6b penetrates readily into the brain and is preferentially localized in the striatum as compared to the cerebellum, the ratio of uptake being 7.2 to 1, 60 min after injection. These observations of good brain penetration and high affinity and selectivity for D-2 receptors indicate that the corresponding iodine-123-labeled benzamide may be a useful ligand for the noninvasive visualization study of dopamine D-2 receptor sites in vivo by single photon emission computed tomography.

Impact of D2 Receptor Internalization on Binding Affinity of Neuroimaging Radiotracers

“…Two-way ANOVA restricted to the imaging agents with conditions (Q-/MTSET- versus Q+/MTSET+) and ligands as factors further revealed a significant effect of conditions (p = 0.003), ligands (p < 0.001) and condition by ligands interactions (p < 0.001). # Calculated with Chemdraw Ultra 11.0.1 (CambridgeSoft, Cambridge, MA). a Laruelle, 2000 b Loc'h et al , 1996 c Kessler et al , 1991 d Wilson et al , 2005 e de Paulis et al , 1988 …”

Synthesis and Structure-Activity Relationships of 4-Amino-5-chloro-N-(1,4-dialkylhexahydro-1,4-diazepin-6-yl)-2-methoxybenzamide Derivatives, Novel and Potent Serotonin 5-HT3 and Dopamine D2 Receptors Dual Antagonist.

“…36b; mp 210. 5 2-Methoxy-4-methylamino-5-nitrobenzoic Acid (37d) In a similar manner to that described above, 2-methoxy-4-[N-methyl-N-(p-toluenesulfonyl)]amino-5-nitrobenzoic acid (36d) was prepared from 35 using fuming HNO 3 (38,4.0 g, 21 mmol), Ac 2 O (10 ml, 0.11 mol), and Et 3 N (1 ml) was stirred at room temperature for 15 h. The reaction mixture was diluted with H 2 O, and then extracted with AcOEt. The extract was washed with brine and concentrated to dryness.…”

The synthesis of dopaminergic radioligands labelled with tritium and iodine‐125

“…81 Also, several benzamide class dopaminergics have been radioiodinated using this versatile methodology as well. [82][83][84][85][86] Although early in this discussion it was mentioned that the relatively small size of dopaminergic substrates usually ruled out the use of most added bulky radiolabelled appendages like the Bolton-Hunter reagent, one prosthetic group that has been successfully employed for radioiodinations is the vinylstannyl group. This labelling option has been exceptionally valuable in preparing target compounds that required radioiodination in positions other than aromatic rings.…”