The dynamic and multicellular processes of neuroinflammation are mediated by the nonneuronal cells of the central nervous system, which include astrocytes and the brain’s resident macrophages, microglia. Although initiation of an inflammatory response may be beneficial in response to injury of the nervous system, chronic or maladaptive neuroinflammation can have harmful outcomes in many neurological diseases. An acute neuroinflammatory response is protective when activated neuroglia facilitate tissue repair by releasing anti-inflammatory cytokines and neurotrophic factors. On the other hand, chronic neuroglial activation is a major pathological mechanism in neurodegenerative diseases, likely contributing to neuronal dysfunction, injury, and disease progression. Therefore, the development of specific and sensitive probes for positron emission tomography (PET) studies of neuroinflammation is attracting immense scientific and clinical interest. An early phase of this research emphasized PET studies of the prototypical imaging biomarker of glial activation, translocator protein-18 kDa (TSPO), which presents difficulties for quantitation and lacks absolute cellular specificity. Many alternate molecular targets present themselves for PET imaging of neuroinflammation in vivo, including enzymes, intracellular signaling molecules as well as ionotropic, G-protein coupled, and immunoglobulin receptors. We now review the lead structures in radiotracer development for PET studies of neuroinflammation targets for neurodegenerative diseases extending beyond TSPO, including glycogen synthase kinase 3, monoamine oxidase-B, reactive oxygen species, imidazoline-2 binding sites, cyclooxygenase, the phospholipase A2/arachidonic acid pathway, sphingosine-1-phosphate receptor-1, cannabinoid-2 receptor, the chemokine receptor CX3CR1, purinergic receptors: P2X7 and P2Y12, the receptor for advanced glycation end products, Mer tyrosine kinase, and triggering receptor expressed on myeloid cells-1. We provide a brief overview of the cellular expression and function of these targets, noting their selectivity for astrocytes and/or microglia, and highlight the classes of PET radiotracers that have been investigated in early-stage preclinical or clinical research studies of neuroinflammation.

Obesity is a global epidemic that contributes to a number of health complications including cardiovascular disease, type 2 diabetes, cancer and neuropsychiatric disorders. Pharmacotherapeutic strategies to treat obesity are urgently needed. Research over the past two decades has increased substantially our knowledge of central and peripheral mechanisms underlying homeostatic energy balance. Homeostatic mechanisms involve multiple components including neuronal circuits, some originating in hypothalamus and brain stem, as well as peripherally-derived satiety, hunger and adiposity signals that modulate neural activity and regulate eating behavior. Dysregulation of one or more of these homeostatic components results in obesity. Coincident with obesity, reward mechanisms that regulate hedonic aspects of food intake override the homeostatic regulation of eating. In addition to functional interactions between homeostatic and reward systems in the regulation of food intake, homeostatic signals have the ability to alter vulnerability to drug abuse. Regarding the treatment of obesity, pharmacological monotherapies primarily focus on a single protein target. FDA-approved monotherapy options include phentermine (Adipex-P®), orlistat (Xenical®), lorcaserin (Belviq®) and liraglutide (Saxenda®). However, monotherapies have limited efficacy, in part due to the recruitment of alternate and counter-regulatory pathways. Consequently, a multi-target approach may provide greater benefit. Recently, two combination products have been approved by the FDA to treat obesity, including phentermine/topiramate (Qsymia®) and naltrexone/bupropion (Contrave®). The current review provides an overview of homeostatic and reward mechanisms that regulate energy balance, potential therapeutic targets for obesity and current treatment options, including some candidate therapeutics in clinical development. Finally, challenges in anti-obesity drug development are discussed.

OBJECTIVE A rat model of diet-induced obesity (DIO) was used to determine dopamine transporter (DAT) function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. DESIGN To evaluate neurobehavioral alterations following the development of DIO induced by an 8-week high-fat diet (HF) exposure, striatal D2-receptor density, DAT function and expression, extracellular dopamine concentrations, impulsivity, and motivation for high- and low-fat reinforcers were determined. To determine predictors of DIO, neurobehavioral antecedents including impulsivity, motivation for high-fat reinforcers, DAT function and extracellular dopamine were evaluated before the 8-week HF exposure. METHODS Striatal D2-receptor density was determined by in vitro kinetic analysis of [3H]raclopride binding. DAT function was determined using in vitro kinetic analysis of [3H]dopamine uptake, methamphetamine-evoked [3H]dopamine overflow and no-net flux in vivo microdialysis. DAT cell-surface expression was determined using biotinylation and western blotting. Impulsivity and food-motivated behavior were determined using a delay discounting task and progressive ratio schedule, respectively. RESULTS Relative to obesity-resistant (OR) rats, obesity-prone (OP) rats exhibited 18% greater body weight following an 8-week HF-diet exposure, 42% lower striatal D2-receptor density, 30% lower total DAT expression, 40% lower in vitro and in vivo DAT function, 45% greater extracellular dopamine and twofold greater methamphetamine-evoked [3H]dopamine overflow. OP rats exhibited higher motivation for food, and surprisingly, were less impulsive relative to OR rats. Impulsivity, in vivo DAT function and extracellular dopamine concentration did not predict DIO. Importantly, motivation for high-fat reinforcers predicted the development of DIO. CONCLUSION Human studies are limited by their ability to determine if impulsivity, motivation and DAT function are causes or consequences of DIO. The current animal model shows that motivation for high-fat food, but not impulsive behavior, predicts the development of obesity, whereas decreases in striatal DAT function are exhibited only after the development of obesity.