Studies on the whole-body distribution of14C-trithioparamethoxyphenylpropene in mice

Abstract Purpose To assess in healthy volunteers the whole-body distribution and dosimetry of [11C]metoclopramide, a new positron emission tomography (PET) tracer to measure P-glycoprotein activity at the blood-brain barrier. Procedures Ten healthy volunteers (five women, five men) were intravenously injected with 387 ± 49 MBq of [11C]metoclopramide after low dose CT scans and were then imaged by whole-body PET scans from head to upper thigh over approximately 70 min. Ten source organs (brain, thyroid gland, right lung, myocardium, liver, gall bladder, left kidney, red bone marrow, muscle and the contents of the urinary bladder) were manually delineated on whole-body images. Absorbed doses were calculated with QDOSE (ABX-CRO) using the integrated IDAC-Dose 2.1 module. Results The majority of the administered dose of [11C]metoclopramide was taken up into the liver followed by urinary excretion and, to a smaller extent, biliary excretion of radioactivity. The mean effective dose of [11C]metoclopramide was 1.69 ± 0.26 μSv/MBq for female subjects and 1.55 ± 0.07 μSv/MBq for male subjects. The two organs receiving the highest radiation doses were the urinary bladder (10.81 ± 0.23 μGy/MBq and 8.78 ± 0.89 μGy/MBq) and the liver (6.80 ± 0.78 μGy/MBq and 4.91 ± 0.74 μGy/MBq) for female and male subjects, respectively. Conclusions [11C]Metoclopramide showed predominantly renal excretion, and is safe and well tolerated in healthy adults. The effective dose of [11C]metoclopramide was comparable to other 11C-labeled PET tracers.

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Whole-body distribution and Malpighian tubule transport of 2′,5-dichloro-4′-nitrosalicylanilide (Bayer 73) and 3-trifluoromethyl-4-nitrophenol in larvae of the aquatic midgeChironomus tentans

Xenobiotica ◽

10.3109/00498258009033753 ◽

1980 ◽

Vol 10 (4) ◽

pp. 257-263 ◽

Cited By ~ 2

Author(s):

C. R. Hansen ◽

J. D. Gauss ◽

J. A. Kawatski

Keyword(s):

Malpighian Tubule ◽

Whole Body ◽

Body Distribution

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Colocalization of ghrelin O-acyltransferase and ghrelin in gastric mucosal cells

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90859.2008 ◽

2009 ◽

Vol 297 (1) ◽

pp. E134-E141 ◽

Cited By ~ 83

Author(s):

Ichiro Sakata ◽

Jing Yang ◽

Charlotte E. Lee ◽

Sherri Osborne-Lawrence ◽

Sherry A. Rovinsky ◽

...

Keyword(s):

Peptide Hormone ◽

Whole Body ◽

Histochemical Analysis ◽

Oxyntic Mucosa ◽

Body Distribution ◽

Naturally Occurring ◽

Mucosal Cells ◽

Membrane Bound ◽

High Degree ◽

Dual Label

Ghrelin is a peptide hormone with many known functions, including orexigenic, blood glucose-regulatory, and antidepressant actions, among others. Mature ghrelin is unique in that it is the only known naturally occurring peptide to be posttranslationally modified by O-acylation with octanoate. This acylation is required for many of ghrelin's actions, including its effects on promoting increases in food intake and body weight. GOAT (ghrelin O-acyltransferase), one of 16 members of the MBOAT family of membrane-bound O-acyltransferases, has recently been identified as the enzyme responsible for catalyzing the addition of the octanoyl group to ghrelin. Although the initial reports of GOAT have localized its encoding mRNA to tissues known to contain ghrelin, it is as yet unclear whether the octanoylation occurs within ghrelin-producing cells or in neighboring cells. Here, we have performed dual-label histochemical analysis on mouse stomach sections and quantitative PCR on mRNAs from highly enriched pools of mouse gastric ghrelin cells to demonstrate a high degree of GOAT mRNA expression within ghrelin-producing cells of the gastric oxyntic mucosa. We also demonstrate that GOAT is the only member of the MBOAT family whose expression is highly enriched within gastric ghrelin cells and whose whole body distribution mirrors that of ghrelin.

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Target Occupancy Study and Whole-Body Dosimetry with a MAGL PET Ligand 11C-PF-06809247 in non-human Primates

10.21203/rs.3.rs-510615/v2 ◽

2021 ◽

Author(s):

Ryosuke Arakawa ◽

Akihiro Takano ◽

Sangram Nag ◽

Zhisheng Jia ◽

Nahid Amini ◽

...

Keyword(s):

Inflammatory Responses ◽

Input Function ◽

Brain Regions ◽

Whole Body ◽

Dependent Manner ◽

Serine Hydrolase ◽

Cynomolgus Monkeys ◽

Pretreatment Condition ◽

Body Distribution ◽

Pretreatment Conditions

Abstract BackgroundMonoacylglycerol lipase (MAGL) is a key serine hydrolase which terminates endocannabinoid signaling and regulates arachidonic acid driven inflammatory responses within the central nervous system (CNS). To develop [11C]PF-06809247 into a clinically usable positron emission tomography (PET) radioligand, we assessed the brain target occupancy of a MAGL inhibitor using non-human primate (NHP). Additionally, we measured the whole-body distribution of [11C]PF-06809247 in NHP and estimated human effective radiation doses.MethodsSeven cynomolgus monkeys were enrolled for brain PET measurements. Two PET measurements were performed in each NHP: one baseline and one pretreatment condition with intravenous administration of PF-06818883, a selective MAGL inhibitor, (total of seven doses between 0.01-1.27 mg/kg). Kinetic parameters K1, k2 and k3 were estimated by an irreversible two tissue compartment (2TC) model using metabolite corrected plasma radioactivity as the input function. Ki by 2TC and Patlak analysis were calculated. The target occupancy was calculated using Ki at baseline and pretreatment conditions. Two cynomolgus monkeys were enrolled for whole-body PET measurements. Estimates of the absorbed radiation dose in humans were calculated with OLINDA/EXM 1.1 using the adult male reference model.ResultsRadioactivity was decreased in all brain regions following pretreatment with PF-06818883. Occupancy was measured as 25.4%-100.5% in a dose dependent manner. Whole-body PET showed high uptake values in the liver, small intestine, kidney, and brain. The effective dose was calculated as 4.3 μSv/MBq.Conclusions[11C]PF-06809247 is a promising PET ligand for further MAGL studies in human brain.

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