1-[2-(2,4-Dimethylphenyl-sulfanyl)-phenyl]-piperazine (Lu AA21004) is a human (h) serotonin (5-HT) 3A receptor antagonist (K i ϭ 3.7 nM), h5-HT 7 receptor antagonist (K i ϭ 19 nM), h5-HT 1B receptor partial agonist (K i ϭ 33 nM), h5-HT 1A receptor agonist (K i ϭ 15 nM), and a human 5-HT transporter (SERT) inhibitor (K i ϭ 1.6 nM) (J Med Chem 54: 3206 -3221, 2011). Here, we confirm that Lu AA21004 is a partial h5-HT 1B receptor agonist [EC 50 ϭ 460 nM, intrinsic activity ϭ 22%] using a whole-cell cAMP-based assay and demonstrate that Lu AA21004 is a rat (r) 5-HT 7 receptor antagonist (K i ϭ 200 nM and IC 50 ϭ 2080 nM). In vivo, Lu AA21004 occupies the r5-HT 1B receptor and rSERT (ED 50 ϭ 3.2 and 0.4 mg/kg, respectively) after subcutaneous administration and is a 5-HT 3 receptor antagonist in the Bezold-Jarisch reflex assay (ED 50 ϭ 0.11 mg/kg s.c.). In rat microdialysis experiments, Lu AA21004 (2.5-10.0 mg/kg s.c.) increased extracellular 5-HT, dopamine, and noradrenaline in the medial prefrontal cortex and ventral hippocampus. Lu AA21004 (5 mg/kg per day for 3 days; minipump subcutaneously), corresponding to 41% rSERT occupancy, significantly increased extracellular 5-HT in the ventral hippocampus. Furthermore, the 5-HT 3 receptor antagonist, ondansetron, potentiated the increase in extracellular levels of 5-HT induced by citalopram. Lu AA21004 has antidepressant-and anxiolytic-like effects in the rat forced swim (Flinders Sensitive Line) and social interaction and conditioned fear tests (minimal effective doses: 7.8, 2.0, and 3.9 mg/kg). In conclusion, Lu AA21004 mediates its pharmacological effects via two pharmacological modalities: SERT inhibition and 5-HT receptor modulation. In vivo, this results in enhanced release of several neurotransmitters and antidepressant-and anxiolytic-like profiles at doses for which targets in addition to the SERT are occupied. The multimodal activity profile of Lu AA21004 is distinct from that of current antidepressants.

Escitalopram is a very selective 5-HT reuptake inhibitor. It is more potent than its racemate citalopram and is effective in animal models predictive of antidepressant and anxiolytic activities.

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Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, and several pharmaceutical companies currently investigate PDE10A inhibitors in clinical trials for various central nervous system diseases. A PDE10A PET ligand may provide evidence that a clinical drug candidate reaches and binds to the target. Here we describe the successful discovery and initial validation of the novel radiolabeled PDE10A ligand 5,8-dimethyl-2-[2-((1-11 C-methyl)-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo [1,5-a]pyridine ( 11 C-Lu AE92686) and its tritiated analog 3 H-Lu AE92686. Methods: Initial in vitro experiments suggested Lu AE92686 as a promising radioligand, and the corresponding tritiated and 11 C-labeled compounds were synthesized. 3 H-Lu AE92686 was evaluated as a ligand for in vivo occupancy studies in mice and rats, and 11 C-Lu AE92686 was evaluated as a PET tracer candidate in cynomolgus monkeys and in humans. Results: 11 C-Lu AE92686 displayed high specificity and selectivity for PDE10A-expressing regions in the brain of cynomolgus monkeys and humans. Similar results were found in rodents using 3 H-Lu AE92686. The binding of 11 C-Lu AE92686 and 3 H-Lu AE92686 to striatum was completely and dose-dependently blocked by the structurally different PDE10A inhibitor 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (MP-10) in rodents and in monkeys. In all species, specific binding of the radioligand was seen in the striatum but not in the cerebellum, supporting the use of the cerebellum as a reference region. The binding potentials (BP ND ) of 11 C-Lu AE92686 in the striatum of both cynomolgus monkeys and humans were evaluated by the simplified reference tissue model with the cerebellum as the reference tissue, and BP ND was found to be high and reproducible-that is, BP ND s were 6.5 ± 0.3 (n 5 3) and 7.5 ± 1.0 (n 5 12) in monkeys and humans, respectively. Conclusion: Rodent, monkey, and human tests of labeled Lu AE92686 suggest that 11 C-Lu AE92686 has great potential as a human PET tracer for the PDE10A enzyme.Key Words: 11 C; 3 H; PET; PDE10A; brain imaging; Lu AE92686 J Nucl Med 2014; 55:1513 55: -1518 55: DOI: 10.2967 Phosphodi esterase 10A (PDE10A) is predominantly expressed in medium spiny neurons and plays a key role in striatal signaling. During the past 10 y, large efforts have been made to develop PDE10A inhibitors for the treatment of schizophrenia (1-3). Preclinical evidence in several animal models suggests that PDE10A inhibitors can improve positive, negative, and cognitive symptoms of schizophrenia, and current clinical trials evaluate PDE10A inhibitors for the treatment of schizophrenia (4). Noninvasive imaging techniques such as PET may be useful for the clinical development of PDE10A inhibitors, because they may provide comparative data on the expression of the enzyme in healthy individuals and in individuals with brain disorders. Furthermore, a PDE10A PET ligand can be used to provide evidence that a clinical drug candidate reaches and bind...

The efficacies of selective 5-HT(2A) and 5-HT(6) receptor antagonists suggest potential mechanisms mediating the effects of sertindole, which has high affinity for these 5-HT receptor subtypes. The sertindole-induced improvement in cognitive function in this animal model suggests relevance for the management of cognitive deficit symptoms in schizophrenia.