Abstract
Brain serotonin-6 receptor (5-HT6R) is the one of the most recently identified serotonin receptors. Accumulating evidence suggests that it is a potent therapeutic target for psychiatric and neurological diseases. Since [18F]2FNQ1P was recently proposed as the first fluorinated positron emission tomography (PET) radioligand for this receptor, the objective of the present study was to demonstrate its suitability for 5-HT6R neuroimaging in primates. [18F]2FNQ1P was characterized by in vitro autoradiography and in vivo PET imaging in cynomolgus monkeys. Following in vivo PET imaging, tracer binding indices were computed using the simplified reference tissue model and Logan graphical model, with cerebellum as reference region. The tracer binding reproducibility was assessed by test–retest in five animals. Finally, specificity was assessed by pre-injection of a 5-HT6R antagonist, SB258585. In vitro, results showed wide cerebral distribution of the tracer with specificity toward 5-HT6Rs as binding was effectively displaced by SB258585. In vivo brain penetration was good with reproducible distribution at cortical and subcortical levels. The automated method gave the best spatial normalization. The Logan graphical model showed the best tracer binding indices, giving the highest magnitude, lowest standard deviation and best reproducibility and robustness. Finally, 5-HT6R antagonist pre-injection significantly decreased [18F]2FNQ1P binding mainly in the striatum and sensorimotor cortex. Taken together, these preclinical results show that [18F]2FNQ1P is a good candidate to address 5-HT6 receptors in clinical studies.
Highlights
Serotonin (5-hydroxytryptamine, 5-HT) is a central neurotransmitter involved in a wide variety of physiological functions, as well as in neurological and psychiatric disorders
Serotonin 5-HT6 receptor (5-HT6R) is one of the most recently discovered serotonin receptors almost exclusively localized in the brain (Woolley et al, 2004). 5-HT6Rs are increasingly reported to be involved in pathophysiological processes and possible therapeutics
A positron emission tomography (PET) tracer is labeled with fluorine 18, which allow transfer to PET nuclear pharmacies and PET imaging centers, allowed thanks to its half-life (T1/2 = 110 min)
Summary
Serotonin (5-hydroxytryptamine, 5-HT) is a central neurotransmitter involved in a wide variety of physiological functions, as well as in neurological and psychiatric disorders. The exclusive [18F]2FNQ1P as a 5-HT6 Radiotracer in Non-human Primates brain localization of this receptor (Woolley et al, 2004), its role at the interface of signaling pathways (Dawson, 2011; Dayer et al, 2015) and, its presence in the pharmacological spectra of several psychotropic drugs have led to the suggestion that it may have applications in the treatment of various psychiatric disorders (Arnt and Olsen, 2011) It appeared that 5-HT6R is involved in memory (Meneses, 2014), cognitive processes (Benhamù et al, 2014) and regulation of food intake (Heal et al, 2011), reinforcing its status as an emerging target for anti-dementia and anti-obesity therapeutic agents. Despite the fact that 5-HT6R functionality is much more complex than initially thought, it is quite evident that this receptor has great pharmaceutical potential in terms of cognition enhancement
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