[¹¹C]TASP0410457, a novel PET ligand for histamine H3 receptors in human brain

Objectives The histamine H3 receptors are presynaptic neuroreceptors and inhibit release of histamine and other nuerotransmitters. The receptors are considered as a drug target for sleep disorders and neuropsychiatric diseases with cognitive decline. We developed a novel PET ligand for the H3 receptors, [¹¹C]TASP0410457, with high affinity, selectivity, and favorable property in monkey and evaluated its kinetics to quantify the H3 receptors in human brain.

Methods Three healthy males were scanned for 120 min with a PET scanner after injection of 388 ± 6.1 MBq of [¹¹C]TASP0410457. Arterial blood sampling and metabolite analyses were performed using a high performance liquid chromatography. Preset volumes of interest were applied on the spatially normalized PET images. The distribution volume for each volume was determined by compartmental analyses and Logan plot.

Results After injection of [¹¹C]TASP0410457, the peak uptake of brain radioactivity was high (SUV ~3-6). The washout was fast in cortical regions and the slowest in the globus pallidus, where the density of the H3 receptors is the highest. Plasma radioactivity showed fast washout, and metabolism of the radioligand was slow (~90% was unmetabolized at 30 min). Distribution volume was well identified using one-tissue compartment model and Logan plot, and its rank was consistent with the known distribution of the H3 receptors with the highest in the globus pallidus (~16 mL/cm3), followed by striatal regions (~8-14), hypothalamus (~9), thalamus (~7), cortical regions (~6-8), and pons (~5).

Conclusions [¹¹C]TASP0410457 is a useful novel PET radioligand to investigate the density of histamine H3 receptors in human brain. The kinetics was very similar to that of monkeys. It can be useful for the evaluation of drug occupancy at the H3 receptors in brain.