Dataset Information

Radiosynthesis, ex Vivo Biodistribution, and in Vivo Positron Emission Tomography Imaging Evaluations of [11C]2-Pyridinealdoxime Methiodide ([11C]2-PAM): A First-In-Class Antidote Tracer for Organophosphate Intoxication.

ABSTRACT: 2-Pyridinealdoxime methiodide (2-PAM) is a widely used antidote for the treatment of organophosphorus (OP) exposure that reactivates the target protein acetylcholinesterase. Carbon-11 2-PAM was prepared to more fully understand the in vivo mode of action, distribution, and dynamic qualities of this important countermeasure. Alkylation of 2-pyridinealdoxime with [11C]CH3I provided the first-in-class [11C]2-PAM tracer in 3.5% decay corrected radiochemical yield from [11C]CH3I, >99% radiochemical purity, and 4831 Ci/mmol molar activity. [11C]2-PAM tracer distribution was evaluated by ex vivo biodistribution and in vivo dynamic positron emission tomography (PET) imaging in naïve (OP exposure deficient) rats. Tracer alone and tracer coinjected with a body mass-scaled human therapeutic dose of 30 mg/kg nonradioactive 2-PAM demonstrated statistically similar tissue and blood distribution profiles with the greatest uptake in kidney and significantly lower levels in liver, heart, and lung with lesser amounts in blood and brain. The imaging and biodistribution data show that radioactivity uptake in brain and peripheral organs is rapid and characterized by differential tissue radioactivity washout profiles. Analysis of arterial blood samples taken 5 min after injection showed ?82% parent [11C]2-PAM tracer. The imaging and biodistribution data are now established, enabling future comparisons to outcomes acquired in OP intoxicated rodent models.

SUBMITTER: Neumann KD

PROVIDER: S-EPMC6699170 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Radiosynthesis, ex Vivo Biodistribution, and in Vivo Positron Emission Tomography Imaging Evaluations of [11C]2-Pyridinealdoxime Methiodide ([11C]2-PAM): A First-In-Class Antidote Tracer for Organophosphate Intoxication.

Neumann Kiel D KD Blecha Joseph E JE Hayes Thomas R TR Huynh Tony T Chao Chih-Kai CK Guilloteau Nicolas N Zinn Kurt R KR VanBrocklin Henry F HF Thompson Charles M CM Gerdes John M JM

ACS chemical neuroscience 20180820 12

2-Pyridinealdoxime methiodide (2-PAM) is a widely used antidote for the treatment of organophosphorus (OP) exposure that reactivates the target protein acetylcholinesterase. Carbon-11 2-PAM was prepared to more fully understand the in vivo mode of action, distribution, and dynamic qualities of this important countermeasure. Alkylation of 2-pyridinealdoxime with [11C]CH3I provided the first-in-class [11C]2-PAM tracer in 3.5% decay corrected radiochemical yield fro ...[more]

PMID: 30071719

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Project description:Excretion of conjugated bile acids into bile is an essential function of the liver, and impairment of canalicular bile acid secretion leads to cholestatic liver injury. However, hepatic excretory function cannot be quantified in vivo because of the lack of suitable methods. Cholylsarcosine is an analog of the endogenous bile acid conjugate cholylglycine and exhibits characteristics in vivo that led us to hypothesize that the (11)C-labeled form, that is, [N-methyl-(11)C]cholylsarcosine ((11)C-cholylsarcosine), would be a suitable PET tracer for quantification of hepatic excretory function.A method for radiosynthesis of (11)C-cholylsarcosine was developed involving (11)C-methylation of glycine followed by conjugation with cholic acid. Blood-to-liver uptake and liver-to-bile excretion were investigated in vivo by dynamic (11)C-cholylsarcosine PET/CT of 2 anesthetized pigs. In pig 1, a second dynamic (11)C-cholylsarcosine PET/CT examination was preceded by a high dose of the endogenous bile acid conjugate cholyltaurine to investigate possible inhibition of the transhepatocellular transport of (11)C-cholylsarcosine. In pig 2, a second (11)C-cholylsarcosine administration was given to determine the biodistribution of the tracer by means of 5 successive whole-body PET/CT recordings. Possible formation of (11)C-metabolites was investigated by analysis of blood and bile samples from a third pig.The radiochemical yield was 13% ± 3% (n = 7, decay-corrected) and up to 1.1 GBq of (11)C-cholylsarcosine was produced with a radiochemical purity greater than 99%. PET/CT studies showed rapid blood-to-liver uptake and liver-to-bile excretion of (11)C-cholylsarcosine, with radioactivity concentrations being more than 90 times higher in the bile ducts than in liver tissue. Cholyltaurine inhibited the transhepatocellular transport of (11)C-cholylsarcosine, indicating that the tracer is transported by one or more of the same hepatic transporters as cholyltaurine. (11)C-cholylsarcosine underwent an enterohepatic circulation and reappeared in liver tissue and bile ducts after approximately 70 min. There were no detectable (11)C-metabolites in the plasma or bile samples, indicating that the novel conjugated bile acid (11)C-cholylsarcosine was not metabolized in the liver or in the intestines. The effective absorbed dose of (11)C-cholylsarcosine was 4.4 ?Sv/MBq.We have synthesized a novel conjugated bile acid analog, (11)C-cholylsarcosine, and PET/CT studies on anesthetized pigs showed that the hepatic handling of tracer uptake from blood and excretion into the bile was comparable to that for the endogenous bile acid cholyltaurine. This tracer may be valuable for future studies of normal and pathologic hepatic excretory functions in humans.

Project description:BACKGROUND:Neuropeptide Y (NPY) has been implicated in a wide variety of physiological processes, including feeding, learning, memory, emotion, cardiovascular homeostasis, hormone secretion, and circadian rhythms. NPY Yl receptor (NPY Y1-R) is the most widely studied NPY receptor, and is involved in many of these processes. BMS-193885 (1) was previously developed as a potent and selective NPY Y1-R antagonist, which has good systemic bioavailability and brain penetration. To evaluate the characteristics of 1 in vivo, we developed 11C-labeled BMS-193885 ([11C]1) and its desmethyl analog ([11C]2) for potential use as two new positron emission tomography (PET) tracers. RESULTS:[11C]1 was synthesized from [11C]methyl iodide using 2. [11C]2 was synthesized from [11C]phosgene using its aniline and amine derivatives. The mean ± S.D. decay-corrected radiochemical yields of [11C]1 and [11C]2 from 11CO2 at the end of radionuclide production were 23 ± 3.2% (n = 6) and 24 ± 1.5% (n = 4), respectively. In biodistribution on mice, radioactivity levels for both tracers were relatively high in the kidney, small intestine, and liver at 60 min post-injection. The radioactivity levels in the kidney, lung, and spleen of mice at 30 min post-injection with [11C]1 were significantly reduced by pretreatment with 1 (10 mg/kg), and levels of [11C]1 in the brain of mice were significantly increased by pretreatment with the P-glycoprotein and breast cancer resistance protein inhibitor elacridar (10 mg/kg). In metabolite analysis using mouse plasma, [11C]1 and [11C]2 were rapidly metabolized within 30 min post-injection, and [11C]1 was mainly metabolized into unlabeled 2 and radiolabeled components. CONCLUSION:[11C]1 and [11C]2 were successfully synthesized with sufficient amount of radioactivity and high quality for use in vivo. Our study of [11C]1 and its desmethyl analog [11C]2 was useful in that it helped to elucidate the in vivo characteristics of 1.

Dataset Information

Radiosynthesis, ex Vivo Biodistribution, and in Vivo Positron Emission Tomography Imaging Evaluations of [11C]2-Pyridinealdoxime Methiodide ([11C]2-PAM): A First-In-Class Antidote Tracer for Organophosphate Intoxication.

Publications

Radiosynthesis, ex Vivo Biodistribution, and in Vivo Positron Emission Tomography Imaging Evaluations of [<sup>11</sup>C]2-Pyridinealdoxime Methiodide ([<sup>11</sup>C]2-PAM): A First-In-Class Antidote Tracer for Organophosphate Intoxication.

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