title: 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.
authors: Merck Research Laboratories, Discovery Imaging Department, West Point, Pennsylvania 19486, USA. terence_hamill@merck.com
authors: Terence G
authors: TG
authors: Hamill
authors: Nagaaki
authors: N
authors: Sato
authors: Makoto
authors: M
authors: Jitsuoka
authors: Shigeru
authors: S
authors: Tokita
authors: Sandra
authors: S
authors: Sanabria
authors: Waisi
authors: W
authors: Eng
authors: Christine
authors: C
authors: Ryan
authors: Stephen
authors: S
authors: Krause
authors: Norihiro
authors: N
authors: Takenaga
authors: Shil
authors: S
authors: Patel
authors: Zhizhen
authors: Z
authors: Zeng
authors: David
authors: D
authors: Williams
authors: Cyrille
authors: C
authors: Sur
authors: Richard
authors: R
authors: Hargreaves
authors: H Donald
authors: HD
authors: Burns
mesh_terms: D000818:Animals; D001345:Autoradiography; D001572:Benzofurans / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002250:Carbon Radioisotopes; D054314:Drug Inverse Agonism; D005462:Fluorine Radioisotopes; D017442:Histamine Agonists / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007553:Isotope Labeling; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D008761:Methylhistamines / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000494:pharmacology*; D018100:Receptors, Histamine H3 / Q000378:metabolism*
chemical_list: C547073:5-(fluoromethoxy)-N-methyl-3-oxo-N-(2-piperidin-1-ylethyl)-3H-spiro(2-benzofuran-1,1'-cyclohexane)-4'-carboxamide; C547072:5-methoxy-N-methyl-3-oxo-N-(2-piperidin-1-ylethyl)-3H-spiro(2-benzofuran-1,1'-cyclohexane)-4'-carboxamide; D001572:Benzofurans; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D017442:Histamine Agonists; D008761:Methylhistamines; D010880:Piperidines; D019275:Radiopharmaceuticals; D018100:Receptors, Histamine H3; C069357:alpha-methylhistamine