CE-123

CE-123 (5-((benzhydrylsulfinyl)methyl)thiazole; CAS 1879038-73-9) is a synthetic modafinil analogue and atypical dopamine transporter (DAT) inhibitor developed at the Department of Pharmaceutical Chemistry, University of Vienna, under the direction of Gert Lubec as part of a structure-activity exploration of heterocyclic diphenylmethylsulfinyl derivatives designed to achieve higher selectivity and affinity at the dopamine transporter than the parent compound modafinil. The active enantiomer, (S)-CE-123, inhibits DAT-mediated dopamine reuptake with an EC50 of approximately 2.76 micromolar in HEK293 cells stably expressing human DAT, with approximately 30-fold selectivity over the norepinephrine transporter (NET) and greater than 400-fold selectivity over the serotonin transporter (SERT). The compound interacts with the outward-facing conformation of DAT to block substrate access without triggering reverse transport or vesicular release, a mechanism that defines the atypical DAT inhibitor class and is associated with lower abuse liability than substrate-type releasers such as amphetamine. Pharmacokinetic characterization in Sprague-Dawley rats demonstrates that (S)-CE-123 achieves an unbound brain-to-plasma concentration ratio (Kp,uu,brain) of 0.5, compared to 0.1 for R-modafinil, indicating approximately five-fold superior blood-brain barrier penetration. Hepatic metabolism proceeds via CYP2C19, CYP3A, and CYP2B6, with a 9.3-fold faster hepatic clearance rate compared to modafinil. The principal metabolite (M1) is formed by hydroxylation of one of the aromatic rings.

The preclinical pharmacology of CE-123 spans multiple cognitive domains tested in several rodent models. In the spatial hole-board paradigm in male Sprague-Dawley rats, daily oral CE-123 at doses of 1 and 10 mg/kg improved both memory acquisition and memory retrieval, with significantly increased reference memory indices and shortened latency to find baited holes. In the attentional set-shifting task, CE-123 at 0.3 and 1.0 mg/kg increased cognitive flexibility (reduced extra-dimensional shift errors) without increasing impulsivity. In aged (26-month) Lister Hooded rats, (S)-CE-123 markedly enhanced motivation and performance in a new-to-learn operant discrimination task and in a cooperation assay of social cognition, with post-treatment proteomic analysis of prefrontal cortex synaptosomes revealing modulation of pathways involved in synaptic vesicle recycling, receptor-mediated endocytosis, and alpha-synuclein membrane localization. In a maternal separation model of early-life stress, CE-123 restored spatial memory deficits in adolescent rats with sex-dependent effects favoring females, and normalized maternal-separation-induced upregulation of DAT and dopamine D1 receptor expression in the prefrontal cortex and hippocampus. In a neonatal ethanol exposure model of fetal alcohol spectrum disorders, CE-123 at 3 and 10 mg/kg attenuated locomotor hyperactivity and ameliorated reversal learning impairment. Neurochemical microdialysis studies in freely moving rats demonstrated that (S)-CE-123 at 10 mg/kg intraperitoneally increased extracellular dopamine in the infralimbic/prelimbic cortex with a pharmacodynamic profile distinct from R-modafinil, and produced only a low and transitory dopamine increase in the nucleus accumbens shell, consistent with reduced reinforcing potential.

No human clinical trials of CE-123 have been published or registered as of the date of this monograph. The compound is not approved by any regulatory authority for human use. It is supplied as a research-grade preparation by multiple chemical vendors at greater than 98 percent purity. A process development and scale-up synthesis has been published (ACS Omega, 2023), establishing a scalable route to the (S)-enantiomer. This monograph reviews the chemistry, synthesis, and stereochemistry of CE-123; the DAT inhibitor pharmacology in molecular and functional detail; the pharmacokinetic characterization including blood-brain barrier penetration; the preclinical cognitive pharmacology across multiple behavioral paradigms and disease models; sourcing and quality verification; reconstitution and handling; stack-interaction considerations; adverse-event signal from preclinical studies; and a comparative assessment of five alternative cognitive-enhancing DAT-active compounds against CE-123 on five competency standards. The compound is strictly a research tool at this stage of development; investigators should obtain analytical confirmation of identity and purity on every lot and should not extrapolate preclinical findings to human dose-response without appropriate regulatory and ethical authorization.