[11C]TASP457, a novel PET ligand for histamine H3 receptors in human brain
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The histamine H3 receptors are presynaptic neuroreceptors that inhibit the release of histamine and other neurotransmitters. The receptors are considered a drug target for sleep disorders and neuropsychiatric disorders with cognitive decline. We developed a novel PET ligand for the H3 receptors, [11C]TASP0410457 ([11C]TASP457), with high affinity, selectivity and favorable kinetic properties in the monkey, and evaluated its kinetics and radiation safety profile for quantifying the H3 receptors in human brain.
Ten healthy men were scanned for 120 min with a PET scanner for brain quantification and three healthy men were scanned for radiation dosimetry after injection of 386 ± 6.2 MBq and 190 ± 7.5 MBq of [11C]TASP457, respectively. For brain quantification, arterial blood sampling and metabolite analysis were performed using high-performance liquid chromatography. Distribution volumes (V T) in brain regions were determined by compartment and graphical analyses using the Logan plot and Ichise multilinear analysis (MA1). For dosimetry, radiation absorbed doses were estimated using the Medical Internal Radiation Dose scheme.
[11C]TASP457 PET showed high uptake (standardized uptake values in the range of about 3 – 6) in the brain and fast washout in cortical regions and slow washout in the pallidum. The two-tissue compartment model and graphical analyses estimated V T with excellent identification using 60-min scan data (about 16 mL/cm3 in the pallidum, 9 – 14 in the basal ganglia, 6 – 9 in cortical regions, and 5 in the pons), which represents the known distribution of histamine H3 receptors. For parametric imaging, MA1 is recommended because of minimal underestimation with small intersubject variability. The organs with the highest radiation doses were the pancreas, kidneys, and liver. The effective dose delivered by [11C]TASP457 was 6.9 μSv/MBq.
[11C]TASP457 is a useful novel PET ligand for the investigation of the density of histamine H3 receptors in human brain.
KeywordsPET quantification Histamine H3 receptors [11C]TASP0410457 [11C]TASP457 Dosimetry
We thank the radiology technologists of the PET Department and members of the Clinical Neuroimaging Team for their support with PET scans, Kazuko Suzuki and Shizuko Kawakami for their assistance as clinical coordinators, Hiromi Sano for her support with MRI scans, the staff of the Molecular Probe Program for radioligand synthesis and metabolite analysis, and Atsuo Waki and his team for quality assurance of the radioligand. The precursor and standard of [11C]TASP457 for this study were provided by Taisho Pharmaceutical Co., Ltd.
Compliance with ethical standards
This study was supported in part by Grants-in-Aid for Scientific Research on Innovative Areas (23111009, 26119531, 26118518) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, Health Labour Sciences Research Grant H25-Seishin-Jituyouka(Seishin)-Ippan-001 from the Ministry of Health, Labour and Welfare, Japan, and the Brain Mapping by Integrated Neurotechnologies for Disease Studies from the Japan Agency for Medical Research and Development.
Conflicts of interest
Y.K., K.T., S.K., M.H. and T.S. are involved in joint research and/or a clinical trial sponsored by Taisho Pharmaceutical Co., Ltd. M.H. and T.S. hold a patent for [11C]TASP457 and related chemicals as H3 ligands (Japan patent JP2014-47209A).
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
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