Reward learning gives rise to strong attentional biases. Stimuli previously associated with reward automatically capture visual attention regardless of intention. Dopamine signaling within the ventral striatum plays an important role in reward learning, representing the expected reward initiated by a cue. How dopamine and the striatum may be involved in maintaining behaviors that have been shaped by reward learning, even after reward expectancies have changed, is less well understood. Nonspecific measures of brain activity have implicated the striatum in value-based attention. However, the neurochemical mechanisms underlying the attentional priority of learned reward cues remain unexplored. Here, we investigated the contribution of dopamine to value-based attention using positron emission tomography (PET) with [(11)C]raclopride. We show that, in the explicit absence of reward, the magnitude of attentional capture by previously reward-associated but currently task-irrelevant distractors is correlated across individuals with changes in available D2/D3 dopamine receptors (presumably due to intrasynaptic dopamine) linked to distractor processing within the right caudate and posterior putamen. Our findings provide direct evidence linking dopamine signaling within the striatum to the involuntary orienting of attention, and specifically to the attention-grabbing quality of learned reward cues. These findings also shed light on the neurochemical basis of individual susceptibility to value-driven attentional capture, which is known to play a role in addiction. More broadly, the present study highlights the value and feasibility of using PET to relate changes in the release of a neurotransmitter to learning-dependent changes in healthy adults.

The physiological functioning of the brain is not well-known in current day medicine and the pathologies of many neuropsychiatric disorders are still not yet fully understood. With our aging population and better life expectancies, it has become imperative to find better biomarkers for disease progression as well as receptor target engagements. In the last decade, these major advances in the field of molecular CNS imaging have been made available with tools such as functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), single photon emission computed tomography (SPECT), and neuroreceptor-targeted positron emission tomography (PET). These tools have given researchers, pharmaceutical companies, and clinical physicians a better method of understanding CNS dysfunctions, and the ability to employ improved therapeutic agents. This review is intended to provide an update on brain imaging agents that are currently used in clinical and translational research toward treatment of CNS disorders. The review begins with amyloid and tau imaging, the former of which has at least three [ 18 F] agents that have been recently approved and will soon be available for clinical use for specific indications in the USA and elsewhere. Other prevalent PET and SPECT neurotransmitter system agents, including those newly US FDA-approved imaging agents related to the dopaminergic system, are included. A review of both mature and potentially growing PET imaging agents, including those targeting serotonin and opiate receptor systems, is also provided.

OBJECTIVE: To compare and contrast the response to dopamine receptor blocking drugs in participants with and without Gilles de la Tourette syndrome (TS) and obsessive-compulsive disorder (OCD). BACKGROUND: Chronic pharmacological doses of dopamine D2/D3 receptor blocking drugs upregulate dopamine D2/D3 receptors. We hypothesized that dopamine D2/D3 receptor blocking drugs upregulate striatal dopamine D2/D3 receptors in patients with TS to a greater degree than patients with OCD and normal controls (Brasic, et al., 2013). To test this hypothesis, we sought to determine if dopamine D2/D3 receptor occupancy differentiates participants with TS and OCD from healthy controls. DESIGN/METHODS: Twenty-one adults (6 controls, 2 TS, 2 OCD, and 11 TS+OCD) underwent positron emission tomography (PET) for 90 minutes (A) after the intravenous injection of 740 MBq (20 mCi) high-specific-activity (HSA) (< 3 micrograms) [11C]raclopride and (B) again four or more days later after the intravenous injection of 740 MBq (20 mCi) low-specific-activity (LSA) (< 600 micrograms) [11C]raclopride. We defined dopamine receptor occupancy = BPHSA - BPLSA ---------------------------- BP HSA where BP = binding potential, HSA = high specific activity, and LSA = low specific activity, in the five subdivisions of the striatum: anterior and posterior caudate nucleus, anterior and posterior putamen, and ventral striatum. RESULTS: The dopamine receptor occupancy was significantly (P < 0.05) greater in patients with TS+OCD than in controls for all brain regions except the posterior caudate nucleus. CONCLUSIONS: Patients with TS+OCD experience a greater occupancy of striatal dopamine D2/D3 receptors after a pharmacological dose of a dopamine receptor blocking drug than normal controls. This finding may explain the limited efficacy of neuroleptics alone in many patients with TS+OCD. Study Supported by: National Institutes of Health (NIH): MH078175, NS38927, K24 DA00412, RO1 AA12839; National Center for Advancing Translational Science (NCATS): UL1RR025005; Tourette Syndrome Association, Inc.; Brain & Behavior Research Foundation (NARSAD); and the Essel Foundation.

The cannabinoid system constitutes a key entity throughout the human body. The cannabinoid type 1 receptor (CB1R), the prominent cannabinoid component in the brain, interacts significantly with the dopaminergic system and its role in reward. CB1Rs have been implicated in “reward disorders” such as obesity and substance abuse, as well as in schizophrenia and mood disorders. The further exploration of the role of these receptors is important for a general knowledge of the brain and, ultimately, for the development of drugs to target associated diseases. Positron emission tomography (PET) imaging allows for the investigation of specific receptors in vivo. PET radioligands targeted to the specific receptor type are essential. The development of effective radiotracers for imaging CB1R has been met with challenges, due to poor blood brain permeability, nonspecificity and fast washout. The current chapter provides a review of the three CB1R PET radioligands available for use to investigate the cannabinoid system in humans in health and disease.

Alzheimer's disease (AD) being the most common form of dementia in individuals over the age of 65 years and with an ever-aging global population, the prevalence of the disease is expected to double in the next 10 years. With the associated high cost, and burden on caregivers, it is imperative that we develop sensitive biomarkers to aid in the diagnosis and treatment for the monitoring of these patients. In recent years, there has been a significant improvement in positron emission tomography (PET) scanner technology and development of new radiotracers that are more target specific. PET imaging of the brain has proven to be the most accurate noninvasive method of not only diagnosing and differentiating the different types of dementia but also predicting the likelihood of developing the disease. Brain PET imaging in combination with pathology may also aid in evaluating the various hypotheses of AD pathogenesis. Although no curative treatment currently exists, the development of novel medications is very much active in many clinical trials. PET imaging will continue to play a significant role in these developments. In this chapter, we will review the various amyloid imaging radiotracers, novel as well as existing, and expand upon their potentials, pitfalls, and relative comparison.

A positron emission tomography (PET) study of dopamine D2 receptor occupancy was conducted to support a rational dose selection for clinical efficacy studies with lurasidone, an atypical antipsychotic that was approved for the treatment of schizophrenia by the FDA in late 2010.

32 Objectives To compare and contrast the differential response to a dopamine receptor blocking drug in healthy normal control subjects, subjects with Gilles de la Tourette syndrome (TS) and obsessive-compulsive disorder (OCD), subjects with TS without OCD, and subjects with OCD without TS. Methods Nineteen subjects aged 18 to 46 (6 healthy controls, 2 TS-only, 2 OCD-only, and 9 TS+OCD) underwent positron emission tomography (PET) for 90 min after the intravenous (IV) administration of high-specific activity [11C]raclopride and again on another day after the IV administration of low-specific activity [11C]raclopride (Wong et al., 2008). Nondisplaceable binding potentials (BPND) were calculated for several regions including the anterior putamen (AP), the posterior putamen (PP), the anterior caudate (AC), the posterior caudate (PC), and the ventral striatum (VS) for each scan. Dopamine blockade (DAB) defined as [HSA(BPND)-LSA(BPND)]/ [HSA(BPND)] was analyzed by nonparametric procedures (StataCorp, 2003). Results Subjects with OCD exhibit less DAB in the AP, PP, AC, and VS. DAB does not differentiate subjects with and without TS (StataCorp, 2003). Equality of populations for healthy subjects, and subjects with TS-only, OCD-only, and TS+OCD was observed (Kruskal-Wallis test)(StataCorp, 2003). Conclusions Reduced DAB in subjects with OCD, but not TS, suggests a characteristic dopaminergic receptor dysfunction in OCD (Brasic et al., 2012). Dopamine receptor blocking drugs may produce less tic suppression in people with TS+OC than in people with TS-only. Research Support PHS grants MH078175, NS38927, DA00412, AA12839, UL1TR000424, The Brain and Behavior Research Foundation (NARSAD), the Essel Foundation, the Tourette Syndrome Association.

UNLABELLED:We evaluated (-)-2-(6-[(18)F]fluoro-2,3'-bipyridin-5'-yl)-7-methyl-7-aza-bicyclo[2.2.1]heptane ((18)F-AZAN), a novel radiotracer that binds to α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) and shows high specific binding and rapid and reversible kinetics in the baboon and human brain. METHODS:We tested safety tolerability and test-retest reliability (n = 5) and proposed initial quantification of (18)F-AZAN receptors in 3 healthy human subjects who had nicotine exposure and 9 who did not. We also present a receptor blocking study in a nicotine subject dosed with the α4β2-nAChR-selective partial agonist varenicline. RESULTS:Radiation dosimetry PET/CT experiments indicated that most human organs received doses between 0.008 and 0.015 mSv/MBq, with an effective dose of approximately 0.014 mSv/MBq. The tracer rapidly entered the brain, and the peak was reached before 20 min, even for thalamus. Ninety-minute scans were sufficient for (18)F-AZAN to obtain the ratio at equilibrium of specifically bound radioligand to nondisplaceable radioligand in tissue (BPND) using plasma reference graphical analysis, which showed excellent reproducibility of BPND (test-retest variability < 10%) in the nAChR-rich brain regions. Regional plasma reference graphical analysis BP(ND) values exceeded 2 in the midbrain tegmental nuclei, lateral geniculate body, and thalamus for nonsmokers (n = 9) but were less than 1 in the nAChR-poor brain regions. There was a dramatic reduction of (18)F-AZAN brain uptake in smokers and varenicline-treated subjects. CONCLUSION:(18)F-AZAN is a highly specific, safe, and effective PET radioligand for human subjects that requires only 90 min of PET scanning to estimate high-affinity α4β2-nAChR in the living human brain.