[18F]FPEB PET imaging of cerebral mGluR5 in health and alcohol-related behaviors

Addiction is a complex brain disorder, leading to a compulsive obsession to use a substance despite serious detrimental consequences. Apart from a dysfunctional reward system, reduced inhibitory corticostriatal control in drug-seeking and drug-taking1 and vulnerability to addiction2 has been emphasized. Genetic, developmental, and environmental factors are major contributors to addiction risk, but the neurobiological processes that underlie vulnerability, craving and relapse are still poorly understood. Aside from the central role of dopamine in reward (intensively studied through availability of suitable PET radioligands3), pharmacological and animal data indicate that glutamate (GLU) plays a pivotal role in drug addiction4. A central role is proposed for metabotropic glutamate receptors (mGluR), especially mGluR55. Downregulation of mGluR5 is thought to be critical in the transition to dependence and in regulation of reward and drug seeking in the mesocorticolimbic motivational circuitry, where it plays a key role in mediating synaptic plasticity pertinent to addiction and interacts with glutamate and dopamine transmission. Specific radioligands have been recently developed for in vivo brain imaging of mGluR5, including 18F-FPEB6, that shows best characteristics regarding signal-to-noise and selectivity. To date, only one human study using mGluR5 PET in addiction (nicotine abuse) has been published, showing a global marked decrease in mGluR5 binding in smokers and to a lesser extend in ex-smokers7. These results support the central role of mGluR5 in addiction and encourage future studies to look at similarities with other types of drug abuse, to assess its potential predictive value for relapse and to explore the interaction with DA and glutamate transmissions. Combined with glutamate magnetic resonance spectroscopy (MRS), dopamine release PET imaging, genetics, temperament and neuropsychological profiling, this project provides a unique window to investigate the determinants of mGluR5 and its modulation of glutamate and dopamine neurotransmission. Apart from pathophysiogical insight into addiction, including craving and relapse, this research may lead to an objective biomarker and tool for proof-of-principle pharmacological treatment. Research hypotheses Our central hypothesis is that in addiction, PET mGluR5 availability is decreased and MRS glutamate levels are regionally increased in the reward circuit (prefrontal cortex, striatum) and that this is common to major forms of substance addiction (alcohol, nicotine and cocaine). Then, we will - test if regional mGluR5 binding is predictive for addiction development and relapse, in detoxified addicts, - investigate the direct interaction of glutamatergic and dopaminergic function by relating mGluR5 availability and GLU levels to DA release capacity in the striatum and frontal cortex by acute administration of drugs of abuse, in low-intensity users, - evaluate if genetics and functional determinants (e.g. executive function and personality traits (especially impulsivity and compulsivity)) are related to these quantitative molecular markers.Table of contents ACKNOWLEDGMENT TABLE OF CONTENTS LIST OF ABBREVIATIONS CHAPTER I: GENERAL INTRODUCTION 1 1.1 THE GLUTAMATERGIC SYSTEM AND MGLUR5 2 1.2 DRUG ADDICTION 4 1.2.1 General aspects and involvement of the glutamatergic system 4 1.2.2 Focus on alcohol dependence 7 1.3 NEUROIMAGING IN ADDICTION 9 1.4 OBJECTIVES AND OVERVIEW OF THE THESIS 10 CHAPTER II: KINETIC MODELLING AND LONG-TERM TEST-RETEST REPRODUCIBILITY OF THE MGLUR5 PET TRACER [18F]FPEB IN HUMAN BRAIN 13 2.1 INTRODUCTION 15 2.2 MATERIALS AND METHODS 16 2.3 RESULTS 20 2.4 DISCUSSION 28 2.5 CONCLUSION 30 CHAPTER III: POSITIVE ASSOCIATION BETWEEN LIMBIC METABOTROPIC GLUTAMATE RECEPTOR 5 AVAILABILITY AND NOVELTY-SEEKING TEMPERAMENT IN HUMANS: A [18F]FPEB PET STUDY 31 3.1 INTRODUCTION 33 3.2 MATERIALS AND METHODS 34 3.3 RESULTS 38 3.4 DISCUSSION 44 3.5 CONCLUSION 47 3.6 SUPPLEMENTAL INFORMATION 48 CHAPTER IV: CEREBRAL DOPAMINERGIC AND GLUTAMATERGIC TRANSMISSION RELATE TO DIFFERENT SUBJECTIVE RESPONSES OF ACUTE ALCOHOL INTAKE: AN IN VIVO MULTIMODAL IMAGING STUDY 55 4.1 INTRODUCTION 57 4.2 MATERIALS AND METHODS 59 4.3 RESULTS 67 4.4 DISCUSSION 74 4.5 CONCLUSION 77 4.6 SUPPLEMENTAL INFORMATION 78 CHAPTER V: DECREASED LIMBIC METABOTROPIC GLUTAMATE RECEPTOR 5 AVAILABILITY IN ALCOHOL DEPENDENCE 81 5.1 INTRODUCTION 83 5.2 MATERIALS AND METHODS 85 5.3 RESULTS 90 5.4 DISCUSSION 96 5.5 CONCLUSION 99 5.6 SUPPLEMENTAL INFORMATION 100 CHAPTER VI: RECOVERY OF DECREASED METABOTROPIC GLUTAMATE RECEPTOR 5 AVAILABILITY IN ABSTINENT ALCOHOL-DEPENDENT SUBJECTS 105 6.1 INTRODUCTION 107 6.2 MATERIALS AND METHODS 109 6.3 RESULTS 113 6.4 DISCUSSION 120 6.5 CONCLUSION 123 6.6 SUPPLEMENTAL INFORMATION 124 CHAPTER VII: GENERAL DISCUSSION, FUTURE PROSPECTS AND FINAL CONCLUSION 129 7.1 GENERAL DISCUSSION 130 7.2 FUTURE PROSPECTS 136 7.3 GENERAL CONCLUSION 139 REFERENCES 140 SUMMARY 157 SAMENVATTING 161 CURRICULUM VITAE 167 LIST OF PUBLICATIONS 169nrpages: 173status: publishe

Clinical experience with 18F-JK-PSMA-7 when using a digital PET/CT

Background Digital PET/CT systems make use of a new technology with higher sensitivity and other better technological features than the analog ones. They require adaptation of the trade-off between performance, tracer dose and acquisition time. The aim of the study was to explore the performance of F-18-JK-PSMA-7 imaging when performed on a digital PET/CT with an adapted protocol, in a population of patients with prostate cancer patients (PCa). Influence of previous therapy on PET/CT performance is generally disregarded in PSMA-based imaging, despite potential influence of hormono-chemotherapy on the target expression. This potential influence was also tested in this work. Methods A total of 54 PCa patients experiencing biochemical recurrence were included in the study, in which we analysed the diagnostic performance of digital F-18-JK-PSMA-7 PET/CT. Compared to our protocol applied for acquisition on an analog system, administered dose and acquisition time were reduced by 20% and 50% respectively. We specifically took into consideration the influence of previous treatments on recurrence detection. Results We detected overall F-18-JK-PSMA-7-positive lesions in 38/54 patients (70.3%). There was no statistically significant difference regarding the detection rate between the groups of patients who had hormono-chemotherapy any time after initial diagnosis and those who never got any hormonal or chemotherapeutic treatment. Regarding the SUV max values, there was not significant difference between the two groups of patients neither in pelvic ganglions nor in other metastatic sites or the prostate region. Conclusion (18F)-JK-PSMA7 PET/CT with administered dose and acquisition time adapted to the digital technology provides valuable information in PCa patients with biochemical recurrence

A first-in-man PET study of [18F]PSS232, a fluorinated ABP688 derivative for imaging metabotropic glutamate receptor subtype 5

ISSN:1619-7070ISSN:1619-708

Abnormalities of Neurotransmission in Drug Addiction

Substance use disorders are prevalent and severe conditions associated with numerous health, social, and economic harms. While the neurobiological mechanisms are still not fully understood, adaptations in multiple neurotransmitter systems have been implicated in the development and maintenance of substance use disorders. The advent of molecular imaging techniques has provided a unique opportunity to better understand abnormalities of neurotransmission in humans with substance use disorders, and this insight may ultimately lead to improved treatment options in the future. This chapter provides a summary of positron emission tomography (PET) and single photon emission computed tomography (SPECT) studies in humans with alcohol, tobacco, cannabis, opioid, and stimulant use disorders. Studies to date provide consistent evidence that the dopaminergic system is disrupted in populations with substance use disorders, although there has been little research in other neurotransmitter systems and findings of existing studies have been mixed. Many PET and SPECT studies investigating abnormalities of neurotransmission in substance use disorder are limited by small sample sizes and over-reliance on male samples without comorbid conditions. In addition, the use of cross-sectional study designs does not make it possible to draw conclusions about causality

Molecular imaging of depressive disorders

This chapter summarizes findings of a large number of molecular imaging studies in the field of unipolar and bipolar depression (BD). Brain metabolism in depressed unipolar and bipolar patients is generally hypoactive in the middle frontal gyri, the pregenual and posterior anterior cingulate, the superior temporal gyrus, the insula, and the cerebellum, while hyperactivity exists in subcortical (caudate nucleus, thalamus), limbic (amygdala, anterior hippocampus), and medial and inferior frontal regions. Interestingly, after depletion of serotonin or noradrenalin/dopamine in vulnerable (recovered) major depressive disorder (MDD) patients, a similar response pattern in metabolism occurs. Findings on the pre-and postsynaptic dopaminergic system show indications that, at least in subgroups of retarded MDD patients, presynaptic dopaminergic markers may be decreased, while postsynaptic markers may be increased. The findings regarding serotonin synthesis, pre-and postsynaptic imaging can be integrated to a presumable loss of serotonin in MDD, while this remains unclear in BD. This reduction of serotonin and dopamine in MDD was recently summarized in a revised version of the monoamine hypothesis, which focuses more on a dysfunction at the level of the MAO enzyme. This should be addressed further in future studies. Nevertheless, it should be acknowledged that the serotonergic and dopaminergic systems appear adaptive; therefore, it remains difficult to distinguish state and trait abnormalities. Therefore, future longitudinal molecular imaging studies in the same subjects at different clinical mood states (preferably with different tracers and imaging modalities) are needed to clarify whether the observed changes in transporters and receptors are compensatory reactions or reflect different, potentially causal mechanisms. Several suggestions for future developments are also provided at the end of this chapter