Inverse agonist histamine H3 receptor PET tracers labelled with carbon‐11 or fluorine‐18

Abstract

Two histamine H3 receptor (H3R) inverse agonist PET tracers have been synthesized and characterized in preclinical studies. Each tracer has high affinity for the histamine H3 receptor, has suitable lipophilicity, and neither is a substrate for the P-glycoprotein efflux pump. A common phenolic precursor was used to synthesize each tracer with high specific activity and radiochemical purity by an alkylation reaction using either [(11)C]MeI or [(18)F]FCD(2)Br. Autoradiographic studies in rhesus monkey and human brain slices showed that each tracer had a widespread distribution with high binding densities in frontal cortex, globus pallidus and striatum, and lower uptake in cerebellum. The specificity of this expression pattern was demonstrated by the blockade of the autoradiographic signal by either the H3R agonist R-alpha-methylhistamine or a histamine H3R inverse agonist. In vivo PET imaging studies in rhesus monkey showed rapid uptake of each tracer into the brain with the same distribution seen in the autoradiographic studies. Each tracer could be blocked by pretreatment with a histamine H3R inverse agonist giving a good specific signal. Comparison of the in vitro metabolism of each compound showed slower metabolism in human liver microsomes than in rhesus monkey liver microsomes, with each compound having a similar clearance rate in humans. The in vivo metabolism of 1b in rhesus monkey showed that at 60 min, approximately 35% of the circulating counts were due to the parent. These tracers are very promising candidates as clinical PET tracers to both study the histamine H3R system and measure receptor occupancy of H3R therapeutic compounds.

11C-MK-8278 PET as a Tool for Pharmacodynamic Brain Occupancy of Histamine 3 Receptor Inverse Agonists

“…Agonist-induced signaling, such as that which occurs in the presence of elevated histamine levels, This study demonstrates the utility of PET scanning to characterize the pharmacodynamic occupancy profile of different potential compounds for the H3 target to inform the rational selection of optimal dosing for future clinical evaluations. In vivo H3 receptor brain distribution using 11 C-MK-8278 was in qualitative agreement with autoradiography data in humans (15) and that reported for 11 C-GSK189254 (16), indicating suitability of the 11 C-MK-8278 for demonstrating H3 receptor sites in the brain in vivo. The development of radioligands for PET imaging of receptors in the CNS is a demanding task, and although binding has been demonstrated for many radioligands for the H3, only a few are suitable for applied quantitative studies.…”

“…2), the highest binding densities were in the ventral pallidal and basal nuclei, nucleus accumbens, substantia nigra, and globus pallidus. Moderate binding was found in other parts of the brain, and the thalamic nuclei (ventral lateral) and brain stem exhibited minimal binding (15). MK-8278 is a poor substrate for human P-glycoprotein, with a transport ratio of 2.3, and shows low plasma protein binding (82% in humans).…”

“…Several selective IA tracers for H3 labeling with 11 C or 18 F have been discovered and evaluated in monkeys (15). Of these, 11 C-MK-8278 is a highly brain-penetrant and selective IA that allows dynamic imaging with fast washout from the brain.…”

Transport of Selected PET Radiotracers by Human P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2): An In Vitro Screening

“…Consequently, a lack of increase in brain uptake obtained with a P-gp modulator does not necessarily mean that there is no P-gp-mediated transport. Some newly developed central nervous system radiotracers designed for histamine H 3 receptor mapping were recently tested in an in vitro model of human P-gp to ensure that they did not interact with P-gp at a preclinical stage (37). However, there is a real need to determine how the compounds used for PET are transported by human P-gp and BCRP (6).…”

When Reversible Ligands Do Not Reverse, and Other Modelers' Dilemmas: FIGURE 1.

“…There is active interest in developing drugs targeted to the H 3 receptor (18); to date, only a few brain-penetrant PET tracers have been reported (19)(20)(21), and all of them are in the early phase of development. In the course of examining 11 C-GSK189254 in human subjects, Ashworth et al (17) observed that the ligand did not reach a washout phase in brain regions where it exhibits high binding, a reference tissue does not exist, and the radioligand is so potent that it is difficult to achieve tracer dose conditions-that is, that 11 C-GSK189254 does not satisfy most of the conditions mentioned here.…”