In vivo comparison of N-11CH3 vs O-11CH3 radiolabeled microtubule targeted PET ligands

Kumar, J.S. Dileep; Prabhakaran, Jaya; Damuka, Naresh; Hines, Justin W.; Norman, Skylar; Dodda, Meghana; Mann, J. John; Mintz, Akiva; Sai, Kiran Kumar Solingapuram

doi:10.1016/j.bmcl.2019.126785

Cited by 6 publications

(5 citation statements)

References 28 publications

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“…[ 11 C]verubulin showed initial brain uptake and decrease in baseline PET measurements in both mouse and rat, consistent with previously reported data in mice (Kumar et al, 2018(Kumar et al, , 2020. The ability to block tubulin binding in mouse has been shown previously using [ 11 C]WX-132-18B and [ 11 C]HD-800 (Sai et al, 2018(Sai et al, , 2020, therefore the decreased radiotracer uptake of [ 11 C]verubulin in mouse is consistent with our expectations.…”

Section: Discussion Pet Imaging In Rodentssupporting

confidence: 92%

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Preliminary Evaluations of [11C]Verubulin: Implications for Microtubule Imaging With PET

et al. 2021

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[11C]Verubulin (a.k.a.[11C]MCP-6827), [11C]HD-800 and [11C]colchicine have been developed for imaging microtubules (MTs) with positron emission tomography (PET). The objective of this work was to conduct an in vivo comparison of [11C]verubulin for MT imaging in mouse and rat brain, as well as an in vitro study with this radiotracer in rodent and human Alzheimer’s Disease tissue. Our preliminary PET imaging studies of [11C]verubulin in rodents revealed contradictory results between mouse and rat brain uptake under pretreatment conditions. In vitro autoradiography with [11C]verubulin showed an unexpected higher uptake in AD patient tissue compared with healthy controls. We also conducted the first comparative in vivo PET imaging study with [11C]verubulin, [11C]HD-800 and [11C]colchicine in a non-human primate. [11C]Verubulin and [11C]HD-800 require pharmacokinetic modeling and quantification studies to understand the role of how these radiotracers bind to MTs before translation to human use.

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Section: Discussion Pet Imaging In Rodentssupporting

confidence: 92%

“…[ 11 C]Verubulin was radiolabeled by O-[ 11 C]methylation using [ 11 C]CH 3 OTf according to a previously published method (Kumar et al, 2020). The product was obtained in 1.5 ± 0.6% radiochemical yield (non-decay corrected (NDC), n = 4), with > 99% radiochemical purity and molar activity of 204 ± 52 GBq/µmol (5.5 ± 1.4 Ci/µmol).…”

Section: Radiochemistrymentioning

confidence: 99%

Preliminary Evaluations of [11C]Verubulin: Implications for Microtubule Imaging With PET

et al. 2021

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“… [3- Methoxy - 11 C]colchicine was radiolabeled by O -[ 11 C]methylation at the 4-position using [ 11 C]CH 3 OTf, with a non-decay correct (ndc) RCY of 0.5%, RCP >99% and A m of 0.389 GBq/μmol (Figure ). , …”

Section: Alkaloidsmentioning

confidence: 99%

Radiosynthesis, Preclinical, and Clinical Positron Emission Tomography Studies of Carbon-11 Labeled Endogenous and Natural Exogenous Compounds

et al. 2022

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The presence of positron emission tomography (PET) centers at most major hospitals worldwide, along with the improvement of PET scanner sensitivity and the introduction of total body PET systems, has increased the interest in the PET tracer development using the short-lived radionuclides carbon-11. In the last few decades, methodological improvements and fully automated modules have allowed the development of carbon-11 tracers for clinical use. Radiolabeling natural compounds with carbon-11 by substituting one of the backbone carbons with the radionuclide has provided important information on the biochemistry of the authentic compounds and increased the understanding of their in vivo behavior in healthy and diseased states. The number of endogenous and natural compounds essential for human life is staggering, ranging from simple alcohols to vitamins and peptides. This review collates all the carbon-11 radiolabeled endogenous and natural exogenous compounds synthesised to date, including essential information on their radiochemistry methodologies and preclinical and clinical studies in healthy subjects.

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“…Previous generations of PET radiotracers reported for MT tracers did not show much uptake in the brain because these tracers are well-characterized substrates of efflux transporters [14]. We screened many microtubule targeting agents (MTAs) as potential PET imaging tracers for MTs and our lead radiotracer [ 11 C]MPC-6827 exhibits high blood brain barrier (BBB) penetration, retention and specific binding in rodent brain (Figure 1) [15,16]. Our pilot preclinical PET imaging studies of […”

Section: Introductionmentioning

confidence: 99%

“…11 C]MPC-6827 was performed using our previously established procedure[15][16][17]. All animal experiments were carried out with the approval of the laboratories and bred and maintained at CUMC[18, 19].…”

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confidence: 99%

Preclinical evaluation of a microtubule PET ligand [11C]MPC-6827 in tau and amyotrophic lateral sclerosis animal models

et al. 2022

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Background: Microtubules are abundant in brain and their malfunctioning occurs in the early to advanced stages of neurodegenerative disorders. At present there is no in vivo test available for a definitive diagnosis of most of the neurodegenerative disorders.Herein, we present the microPET imaging of microtubules using our recently reported Positron Emission Tomography (PET) tracer, [ 11 C]MPC-6827, in transgenic mice models of tau pathology (rTg4510) and amyotrophic lateral sclerosis pathology (SOD1*G93A) and compared to corresponding age matched controls. Methods: Automated synthesis of [ 11 C]MPC-6827 was achieved in a GE-FX2MeI/FX2M radiochemistry module. In vivo PET imaging studies of [ 11 C]MPC-6827 (3.7+0.8 MBq)were performed in rTg4510 and SOD1*G93A mice groups and their corresponding littermates (n=5 per group). Dynamic PET images were acquired using a microPET Inveon system (Siemens, Germany) at 55 minutes for rTg4510 and 30 minutes for SOD1*G93A and corresponding controls. PET images were reconstructed using the 3D-OSEM algorithm and analyzed using VivoQuant version 4 (Invicro, MA). Tracer uptake in ROIs that included whole brain was measured as %ID/g over time to generate standardized uptake values (SUV) and time-activity curves (TACs).Results: [ 11 C]MPC-6827 exhibit a trend of lower tracer binding in mouse models of Alzheimer's disease (tau pathology, line rTg4510) and Amyotrophic Lateral Sclerosis (line SOD1*G93A) compared to wild type littermates. Conclusions:Our finding indicates a trend of loss of microtubule binding of [ 11 C]MPC-6827 in the whole brain of AD and ALS transgenic mice models compared to control mice.The pilot studies described herein show that [ 11 C]MPC-6827 could be used as a PET ligand for preclinical and human brain imaging of Alzheimer's disease, ALS and other neurodegenerative diseases.

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In vivo comparison of N-11CH3 vs O-11CH3 radiolabeled microtubule targeted PET ligands

Cited by 6 publications

References 28 publications

Preliminary Evaluations of [11C]Verubulin: Implications for Microtubule Imaging With PET

Preliminary Evaluations of [11C]Verubulin: Implications for Microtubule Imaging With PET

Radiosynthesis, Preclinical, and Clinical Positron Emission Tomography Studies of Carbon-11 Labeled Endogenous and Natural Exogenous Compounds

Preclinical evaluation of a microtubule PET ligand [11C]MPC-6827 in tau and amyotrophic lateral sclerosis animal models

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