¹¹C‐labeled and ¹⁸F‐labeled PET ligands for subtype‐specific imaging of histamine receptors in the brain

Abstract

The signaling molecule histamine plays a key role in the mediation of immune reactions, in gastric secretion, and in the sensory system. In addition, it has an important function as a neurotransmitter in the central nervous system, acting in pituitary hormone secretion, wakefulness, motor and cognitive functions, as well as in itch and nociception. This has raised interest in the role of the histaminergic system for the treatment and diagnosis of various pathologies such as allergy, sleeping and eating disorders, neurodegeneration, neuroinflammation, mood disorders, and pruritus. In the past 20 years, several ligands targeting the four different histamine receptor subtypes have been explored as potential radiotracers for positron emission tomography (PET). This contribution provides an overview of the developments of subtype-selective carbon-11-labeled and fluorine-18-labeled compounds for imaging in the brain. Using specific radioligands, the H1 R expression in human brain could be examined in diseases such as schizophrenia, depression, and anorexia nervosa. In addition, the sedative effects of antihistamines could be investigated in terms of H1 R occupancy. The H3 R is of special interest because of its regulatory role in the release of various other neurotransmitters, and initial H3 R PET imaging studies in humans have been reported. The H4 R is the youngest member of the histamine receptor family and is involved in neuroinflammation and various sensory pathways. To date, two H4 R-specific (11) C-labeled ligands have been synthesized, and the imaging of the H4 R in vivo is in the early stage.

Application of cross-species PET imaging to assess neurotransmitter release in brain

“…Here, we have discussed in detail the progress made for PET measurement of dopamine, serotonin, noradrenaline, GABA, glutamate, ACh, and opioid peptides. In addition to the aforementioned investigation utilizing PDE10A radioligands to measure changes in cyclic nucleotides, ongoing activity towards the development of PET radioligands for GPCR histamine receptor subtypes H 1 to H 4 (for review see Funke et al 2013 ) may soon provide radioligand tools which are sensitive to measuring endogenous histamine levels. The H 1 receptor antagonist [ 11 C]doxepin and the H 3 receptor antagonists [ 11 C]GSK189254 (Ashworth et al 2010 ) and [ 11 C]MK8278 (Van Laere et al 2014 ) have been successfully characterized in human PET studies, but so far no reports exist in which these radioligands have been utilized for assessment of drug-induced changes in extracellular histamine levels.…”

Imaging neuroinflammation in multiple sclerosis using TSPO-PET

“…Cannabinoid receptor 2 (CB2) is also expressed in activated microglia [ 80 ], and consequently, numerous ligands have recently been developed and pre-clinically tested [ 81 – 84 ]. In addition, histamine 4 (H4) and cyclo-oxygenase 2 (COX-2) receptors being involved also in neuroinflammation, and folate receptors being linked to many inflammatory and autoimmune diseases, appear as interesting future targets for PET imaging of neuroinflammation [ 85 – 87 ].…”

PET Radioligands for In Vivo Visualization of Neuroinflammation

“…Other H 4 R ligands have been developed by Strakhova et al [226], Sander et al [227], Savall et al [228], Mowbray et al [229] and Lane et al [230] and are also interesting for labeling with carbon-11 or fluorine-18. Two of the mentioned lead structures, JNJ7777120 and VUF10558, were radiolabeled with carbon-11 and currently, [ 11 C]JNJ7777120 is being evaluated in vivo [231].…”