FAUC 346 is a Highly Selective D3 Partial Agonist

Dopamine receptors are classified into the Gs-coupled D1-like (D1 and D5) and Gi/o-coupled D2-like (D2, D3, and D4) receptor subtypes. FAUC 346 is an in vitro D3-selective ligand. In particular, selective D3 ligands may have therapeutic potential for the treatment of drug addiction and Parkinson’s disease.

Dopamine D3 receptors (D3R) modulate neuronal activity in several brain regions including cortex, striatum, cerebellum, and hippocampus. Indeed, D3R can modulate neural activity by acting on neurotransmitter receptors. Moreover, FAUC 346 presents a good affinity for D3 receptors (cloned human dopamine receptors stably expressed in CHO cells; Ki=0.23 nM). Furthermore, FAUC 346 displays high selectivity for D3 receptor over other D2-like receptors [Ki(D2/D3)=380; Ki(D4/D3)=65]. FAUC 346 demonstrates an inhibitory effect on cocaine-seeking behavior. In addition, FAUC 346 also shows some affinity for 5HT1A receptors (Ki=41 nM) and for α1 receptors (Ki=15 nM).

FAUC 346 could be a suitable tracer for D3 receptors. Preliminary pharmacological evaluation of [11C]FAUC 346 in rat brain clearly demonstrates in vivo selectivity for D3 receptors and the absence of radiolabeled metabolite within the brain. Pretreatment of FAUC 346 (1 mg/kg i.p., 30 min before injection of the radiotracer) in a series of rats for nonspecific binding. As a result, the rats are intravenously injected with 3.7-4.0 MBq (0.08–0.12 nmol) of [11C]-FAUC 346 and sacrificed 30 min later. Inhibition of the uptake of [11C]-FAUC 346 reaches about 80% in all observed brain regions, compared with untreated animals.

All in all, FAUC 346 is a high affinity (Ki=0.23 nM), potent (EC50=1.5 nM) and highly selective D3 partial agonist.

Bertrand Kuhnast, et al. Synthesis and radiolabeling of N-[4-[4-(2-[11C]methoxyphenyl)piperazin-1-yl]butyl]benzo[b]thiophene-2-carboxamide——a potential radiotracer for D3 receptor imaging with PET. Nucl Med Biol. 2006 Aug;33(6):785-95.