Beyond monoamines: I. Novel targets and radiotracers for Positron emission tomography imaging in psychiatric disorders

Abstract

With the emergence of positron emission tomography (PET) in the late 1970s, psychiatry had access to a tool capable of non‐invasive assessment of human brain function. Early applications in psychiatry focused on identifying characteristic brain blood flow and metabolic derangements using radiotracers such as [15O]H2O and [18F]FDG. Despite the success of these techniques, it became apparent that more specific probes were needed to understand the neurochemical bases of psychiatric disorders. The first neurochemical PET imaging probes targeted sites of action of neuroleptic (dopamine D2 receptors) and psychoactive (serotonin receptors) drugs. Based on the centrality of monoamine dysfunction in psychiatric disorders and the measured success of monoamine‐enhancing drugs in treating them, the next 30 years witnessed the development of an armamentarium of PET radiopharmaceuticals and imaging methodologies for studying monoamines. Continued development of monoamine‐enhancing drugs over this time however was less successful, realizing only modest gains in efficacy and tolerability. As patent protection for many widely prescribed and profitable psychiatric drugs lapsed, drug development pipelines shifted away from monoamines in search of novel targets with the promises of improved efficacy, or abandoned altogether. Over this period, PET radiopharmaceutical development activities closely paralleled drug development priorities resulting in the development of new PET imaging agents for non‐monoamine targets. Part one of this review will briefly survey novel PET imaging targets with relevance to the field of psychiatry, which include the metabotropic glutamate receptor type 5 (mGluR5), purinergic P2X7 receptor, type 1 cannabinoid receptor (CB1), phosphodiesterase 10A (PDE10A), and describe radiotracers developed for these and other targets that have matured to human subject investigations. Current limitations of the targets and techniques will also be discussed.

Positron Emission Tomography for the Discovery of New Drugs in Psychiatry

“…It is therefore possible to visualize, quantify, and longitudinally follow almost all the pharmacological targets of current psychiatric drugs. Ongoing development of new radiotracers also opens the field to prospective studies for potential targets in psychiatry (serotonin 5-HT 6 receptor, metabotropic glutamate receptor type 5, type 1 cannabinoid receptor, to name but a few). Although biological psychiatry no longer considers that a given pathology implicates a single receptor, PET imaging of neurotransmission markers during the course of a pathology is nevertheless an essential approach.…”

Preclinical and clinical imaging techniques as pathophysiological biomarkers — A preface to the special issue “Brain Imaging”

“…Astrogliosis is not only an early neuroinflammatory event in several neurodegenerative conditions such as AD, but also represents a spectrum of molecular, morphological and functional changes characterized by a loss of normal protective function and a gain of toxic function as they respond to CNS insults (Kumar et al, 2021). Researchers at the University of Pittsburgh tackle the vast and complex issues related to the use of PET in psychiatric conditions (Lopresti et al, 2022; Royse et al, 2022). In the first part they recapitulate the history of PET in psychiatry with the study of dopamine and serotonin and then move beyond monoamines concentrating on novel probes for the assessment of synaptic neurotransmitters and receptors, enzymes as well as those tracers developed for assessing neuroinflammation (Lopresti et al, 2022).…”

“…Preclinical approaches allow the examination in real time of synaptic and intracellular signaling events in single and multiple neurons and their relationship to behavior, permitting a deeper mechanistic insight into brain function (Day-Cooney et al, 2022;Guo et al, 2022). Clinical applications using a wide variety of probes allow the assessment of proteinopathies (Hoenig & Drzezga, 2022), neuroinflammation (Kumar et al, 2021), the integrity of the nigrostriatal dopaminergic pathway (Nicastro et al, 2021), as well as the examination of neurotransmitter and neuroreceptor imaging in psychiatric disorders (Lopresti et al, 2022;Royse et al, 2022). complex issues related to the use of PET in psychiatric conditions (Lopresti et al, 2022;Royse et al, 2022).…”

“…Clinical applications using a wide variety of probes allow the assessment of proteinopathies (Hoenig & Drzezga, 2022), neuroinflammation (Kumar et al, 2021), the integrity of the nigrostriatal dopaminergic pathway (Nicastro et al, 2021), as well as the examination of neurotransmitter and neuroreceptor imaging in psychiatric disorders (Lopresti et al, 2022;Royse et al, 2022). complex issues related to the use of PET in psychiatric conditions (Lopresti et al, 2022;Royse et al, 2022). In the first part they recapitulate the history of PET in psychiatry with the study of dopamine and serotonin and then move beyond monoamines concentrating on novel probes for the assessment of synaptic neurotransmitters and receptors, enzymes as well as those tracers developed for assessing neuroinflammation (Lopresti et al, 2022).…”

“…complex issues related to the use of PET in psychiatric conditions (Lopresti et al, 2022;Royse et al, 2022). In the first part they recapitulate the history of PET in psychiatry with the study of dopamine and serotonin and then move beyond monoamines concentrating on novel probes for the assessment of synaptic neurotransmitters and receptors, enzymes as well as those tracers developed for assessing neuroinflammation (Lopresti et al, 2022).…”