Neumann KD

References (2)

Title : Radiosynthesis, ex Vivo Biodistribution, and in Vivo Positron Emission Tomography Imaging Evaluations of [(11)C]2-Pyridinealdoxime Methiodide ([(11)C]2-PAM): A First-In-Class Antidote Tracer for Organophosphate Intoxication - Neumann_2018_ACS.Chem.Neurosci_9_3007
Author(s) : Neumann KD , Blecha JE , Hayes TR , Huynh T , Chao CK , Guilloteau N , Zinn KR , VanBrocklin HF , Thompson CM , Gerdes JM
Ref : ACS Chem Neurosci , 9 :3007 , 2018
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 [(11)C]CH3I provided the first-in-class [(11)C]2-PAM tracer in 3.5% decay corrected radiochemical yield from [(11)C]CH3I, >99% radiochemical purity, and 4831 Ci/mmol molar activity. [(11)C]2-PAM tracer distribution was evaluated by ex vivo biodistribution and in vivo dynamic positron emission tomography (PET) imaging in naive (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 approximately 82% parent [(11)C]2-PAM tracer. The imaging and biodistribution data are now established, enabling future comparisons to outcomes acquired in OP intoxicated rodent models.
ESTHER : Neumann_2018_ACS.Chem.Neurosci_9_3007
PubMedSearch : Neumann_2018_ACS.Chem.Neurosci_9_3007
PubMedID: 30071719

Title : An improved radiosynthesis of O-(2-[18 F]fluoroethyl)-O-(p-nitrophenyl)methylphosphonate: A first-in-class cholinesterase PET tracer - Neumann_2017_J.Labelled.Comp.Radiopharm_60_337
Author(s) : Neumann KD , Thompson CM , Blecha JE , Gerdes JM , VanBrocklin HF
Ref : J Labelled Comp Radiopharm , 60 :337 , 2017
Abstract : O-(2-Fluoroethyl)-O-(p-nitrophenyl) methylphosphonate 1 is an organophosphate cholinesterase inhibitor that creates a phosphonyl-serine covalent adduct at the enzyme active site blocking cholinesterase activity in vivo. The corresponding radiolabeled O-(2-[18 F]fluoroethyl)-O-(p-nitrophenyl) methylphosphonate, [18 F]1, has been previously prepared and found to be an excellent positron emission tomography imaging tracer for assessment of cholinesterases in live brain, peripheral tissues, and blood. However, the previously reported [18 F]1 tracer synthesis was slow even with microwave acceleration, required high-performance liquid chromatography separation of the tracer from impurities, and gave less optimal radiochemical yields. In this paper, we report a new synthetic approach to circumvent these shortcomings that is reliant on the facile reactivity of bis-(O,O-p-nitrophenyl) methylphosphonate, 2, with 2-fluoroethanol in the presence of DBU. The cold synthesis was successfully translated to provide a more robust radiosynthesis. Using this new strategy, the desired tracer, [18 F]1, was obtained in a non-decay-corrected radiochemical yield of 8 +/- 2% (n = 7) in >99% radiochemical and >95% chemical purity with a specific activity of 3174 +/- 345 Ci/mmol (EOS). This new facile radiosynthesis routinely affords highly pure quantities of [18 F]1, which will further enable tracer development of OP cholinesterase inhibitors and their evaluation in vivo.
ESTHER : Neumann_2017_J.Labelled.Comp.Radiopharm_60_337
PubMedSearch : Neumann_2017_J.Labelled.Comp.Radiopharm_60_337
PubMedID: 28406525