Improved Chemical and Radiochemical Synthesis of Neuropeptide Y Y2 Receptor Antagonist N-Methyl-JNJ-31020028 and Preclinical Positron Emission Tomography Studies.

Neuropeptide Y (NPY) is one of the most abundant peptides in the central nervous system of mammals and is involved in several physiological processes through NPY Y1, Y2, Y4 and Y5 receptors. Of those, the Y2 receptor has particular relevance for its autoreceptor role in inhibiting the release of NPY and other neurotransmitters and for its involvement in relevant mechanisms such as feeding behaviour, cognitive processes, emotion regulation, circadian rhythms and disorders such as epilepsy and cancer. PET imaging of the Y2 receptor can provide a valuable platform to understand this receptor's functional role and evaluate its potential as a therapeutic target. In this work, we set out to refine the chemical and radiochemical synthesis of the Y2 receptor antagonist N-[11C]Me-JNJ31020028 for in vivo PET imaging studies. The non-radioactive reference compound, N-Me-JNJ-31020028, was synthesised through batch synthesis and continuous flow methodology, with 43% and 92% yields, respectively. N-[11C]Me-JNJ-31020028 was obtained with a radiochemical purity > 99%, RCY of 31% and molar activity of 156 GBq/µmol. PET imaging clearly showed the tracer's biodistribution in several areas of the mouse brain and gut where Y2 receptors are known to be expressed.

Sex Differences in Tryptophan Metabolism: A Systematic Review Focused on Neuropsychiatric Disorders.

Tryptophan (Tryp) is an essential amino acid and the precursor of several neuroactive compounds within the central nervous system (CNS). Tryp metabolism, the common denominator linking serotonin (5-HT) dysfunctions and neuroinflammation, is involved in several neuropsychiatric conditions, including neurological, neurodevelopmental, neurodegenerative, and psychiatric diseases. Interestingly, most of those conditions occur and progress in a sex-specific manner. Here, we explore the most relevant observations about the influence of biological sex on Tryp metabolism and its possible relation to neuropsychiatric diseases. Consistent evidence suggests that women have a higher susceptibility than men to suffer serotoninergic alterations due to changes in the levels of its precursor Tryp. Indeed, female sex bias in neuropsychiatric diseases is involved in a reduced availability of this amino acid pool and 5-HT synthesis. These changes in Tryp metabolism could lead to sexual dimorphism on the prevalence and severity of some neuropsychiatric disorders. This review identifies gaps in the current state of the art, thus suggesting future research directions. Specifically, there is a need for further research on the impact of diet and sex steroids, both involved in this molecular mechanism as they have been poorly addressed for this topic.

Single Low Dose of Cocaine-Structural Brain Injury Without Metabolic and Behavioral Changes.

Chronic cocaine use has been shown to lead to neurotoxicity in rodents and humans, being associated with high morbidity and mortality rates. However, recreational use, which may lead to addictive behavior, is often neglected. This occurs, in part, due to the belief that exposure to low doses of cocaine comes with no brain damage risk. Cocaine addicts have shown glucose metabolism changes related to dopamine brain activity and reduced volume of striatal gray matter. This work aims to evaluate the morphological brain changes underlying metabolic and locomotor behavioral outcome, in response to a single low dose of cocaine in a pre-clinical study. In this context, a Balb-c mouse model has been chosen, and animals were injected with a single dose of cocaine (0.5 mg/kg). Control animals were injected with saline. A behavioral test, positron emission tomography (PET) imaging, and anatomopathological studies were conducted with this low dose of cocaine, to study functional, metabolic, and morphological brain changes, respectively. Animals exposed to this cocaine dose showed similar open field activity and brain metabolic activity as compared with controls. However, histological analysis showed alterations in the prefrontal cortex and hippocampus of mice exposed to cocaine. For the first time, it has been demonstrated that a single low dose of cocaine, which can cause no locomotor behavioral and brain metabolic changes, can induce structural damage. These brain changes must always be considered regardless of the dosage used. It is essential to alert the population even against the consumption of low doses of cocaine.