[18F]KS1, a novel ascorbate-based ligand images ROS in tumor models of rodents and nonhuman primates

Damuka, Naresh; Bashetti, Nagaraju; Mintz, Akiva; Bansode, Avinash; Miller, Mack; Krizan, Ivan; Furdui, Cristina M.; Bhoopal, Bhuvanachandra; Gollapelli, Krishna Kumar; Kumar, JV Shanmukha; Deep, Gagan; Dugan, Greg; Cline, Mark A.; Sai, Kiran Kumar Solingapuram

doi:10.1016/j.biopha.2022.113937

Cited by 3 publications

(1 citation statement)

References 60 publications

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“…, 60 min post radiotracer administration, the mice were euthanized. Samples of brain, blood, brain, heart, lung, liver, spleen, pancreas, kidney, intestine, and muscle were harvested, weighed, and γ-counted using a Wallac Automatic γ Counter with a standard dilution of the injectate following our previous protocols. , Percentages of the injected dose per gram of tissue (%ID/g) , were calculated.…”

Section: Methodsmentioning

confidence: 99%

First GPR119 PET Imaging Ligand: Synthesis, Radiochemistry, and Preliminary Evaluations

Bansode,

Damuka,

Bashetti

et al. 2023

J. Med. Chem.

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G-protein-coupled receptor 119 (GPR119) has emerged as a promising target for treating type 2 diabetes mellitus. Activating GPR119 improves glucose homeostasis, while suppressing appetite and weight gain. Measuring GPR119 levels in vivo could significantly advance GPR119-based drug development strategies including target engagement, occupancy, and distribution studies. To date, no positron emission tomography (PET) ligands are available to image GPR119. In this paper, we report the synthesis, radiolabeling, and preliminary biological evaluations of a novel PET radiotracer [18F]KSS3 to image GPR119. PET imaging will provide information on GPR119 changes with diabetic glycemic loads and the efficacy of GPR119 agonists as antidiabetic drugs. Our results demonstrate [18F]KSS3’s high radiochemical purity, specific activity, cellular uptake, and in vivo and ex vivo uptake in pancreas, liver, and gut regions, with high GPR119 expression. Cell pretreatment with nonradioactive KSS3, rodent PET imaging, biodistribution, and autoradiography studies showed significant blocking in the pancreas showing [18F]KSS3’s high specificity.

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Section: Methodsmentioning

confidence: 99%

First GPR119 PET Imaging Ligand: Synthesis, Radiochemistry, and Preliminary Evaluations

Bansode,

Damuka,

Bashetti

et al. 2023

J. Med. Chem.

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Exploring microtubule dynamics in Alzheimer's disease: Longitudinal assessment using [¹¹C]MPC‐6827 PET imaging in rodent models of Alzheimer's‐related pathology

Damuka,

Irmen,

Krizan

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONMicrotubule (MT) stability is crucial for proper neuronal function. Understanding MT dysregulation is critical for connecting amyloid beta (Aβ) and tau‐based degenerative events and early changes in presymptomatic Alzheimer's disease (AD). Herein we present positron emission tomography (PET) imaging properties of our MT‐PET radiotracer, [11C]MPC‐6827, in multiple established AD mouse models.METHODSLongitudinal PET, biodistribution, autoradiography, immunohistochemistry, and behavioral studies were conducted at multiple time points in APPswe/PSEN1dE9 (APP/PS1), P301S‐PS19 (P301S), 5xFAD, and age‐matched control mice.RESULTSLongitudinal [11C]MPC‐6827 brain imaging showed significant increases in APP/PS1, P301S, and 5xFAD mice compared to controls. Longitudinal MT‐PET correlated positively with biodistribution, autoradiography, and immunohistochemistry results and negatively with behavior data.DISCUSSIONOur study demonstrated significant longitudinal [11C]MPC‐6827 PET increases in multiple AD mouse models for the first time. Strong correlations between PET and biomarker data underscored the interplay of MT destabilization, amyloid, and tau pathology in AD. These results suggest [11C]MPC‐6827 PET as a promising tool for monitoring MT dysregulation early in AD progression.Highlights Longitudinal positron emission tomography (PET) imaging studies using [11C]MPC‐6827 in multiple established Alzheimer's disease (AD) mouse models revealed an early onset of microtubule dysregulation, with significant changes in brain radiotracer uptake evident from 2 to 4 months of age. Intra‐group analysis showed a progressive increase in microtubule dysregulation with increasing AD burden, supported by significant correlations between PET imaging data and biodistribution, autoradiography, and molecular pathological markers. [11C]MPC‐6827 PET imaging demonstrated its efficacy in detecting early microtubule alterations preceding observable behavioral changes in AD mouse models, suggesting its potential for early AD imaging. The inclusion of the 5xFAD mouse model further elucidated the impact of amyloid beta (Aβ) toxicity on inducing tau hyperphosphorylation‐mediated microtubule dysregulation, highlighting the versatility of [11C]MPC‐6827 in delineating various aspects of AD pathology. Our study provides immediate clarity on high uptake of the microtubule‐based radiotracer in AD brains in a longitudinal setting, which directly informs clinical utility in Aβ/tau‐based studies.

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Application of copper (I) selective ligands for PET imaging of reactive oxygen species through metabolic trapping

Tada,

Mizuno,

Shibata

et al. 2024

Nuclear Medicine and Biology

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[18F]KS1, a novel ascorbate-based ligand images ROS in tumor models of rodents and nonhuman primates

Cited by 3 publications

References 60 publications

First GPR119 PET Imaging Ligand: Synthesis, Radiochemistry, and Preliminary Evaluations

First GPR119 PET Imaging Ligand: Synthesis, Radiochemistry, and Preliminary Evaluations

Exploring microtubule dynamics in Alzheimer's disease: Longitudinal assessment using [¹¹C]MPC‐6827 PET imaging in rodent models of Alzheimer's‐related pathology

Application of copper (I) selective ligands for PET imaging of reactive oxygen species through metabolic trapping

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[18F]KS1, a novel ascorbate-based ligand images ROS in tumor models of rodents and nonhuman primates

Cited by 3 publications

References 60 publications

First GPR119 PET Imaging Ligand: Synthesis, Radiochemistry, and Preliminary Evaluations

First GPR119 PET Imaging Ligand: Synthesis, Radiochemistry, and Preliminary Evaluations

Exploring microtubule dynamics in Alzheimer's disease: Longitudinal assessment using [11C]MPC‐6827 PET imaging in rodent models of Alzheimer's‐related pathology

Application of copper (I) selective ligands for PET imaging of reactive oxygen species through metabolic trapping

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Exploring microtubule dynamics in Alzheimer's disease: Longitudinal assessment using [¹¹C]MPC‐6827 PET imaging in rodent models of Alzheimer's‐related pathology