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

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 20years, several ligands targeting the four different histamine receptor subtypes have been explored as potential radiotracers for positron emission tomography. 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, we could examine the H1R expression in the human brain in diseases such as schizophrenia, depression, and anorexia nervosa. In addition, the sedative effects of antihistamines could be investigated in terms of H1R occupancy. The H3R is of special interest because of its regulatory role in the release of various other neurotransmitters, and initial H3R positron emission tomography imaging studies in humans have been reported. The H4R is the youngest member of the histamine receptor family and is involved in neuroinflammation and various sensory pathways. To date, two H4R-specific 11C-labeled ligands have been synthesized, and the imaging of the H4R in vivo is in the early stage.