Azixa (verubulin) / Immune Pharma - LARVOL DELTA

11C-MPC6827 in vivo binding to microtubules in human brain: a first test-retest study in humans (SNMMI 2025) - "For the four same-day test-retest participants, across methods and scan durations, 11C-MPC6827 VT estimates in whole brain showed PD values ranging from 9.34±7.79% to 18.01±10.32% (average±standard deviation across participants), and ICC values between 0.75 and 0.94 (Figure 1). Time-stability analysis shows that VT estimates were stable as the scanning time shortens for all considered methods and regions, with average VT shorter scan/VT 90 min ratios (across scans) between 1 and 1.03 (Figure 2). Kinetic models provided higher time-stability than graphical approaches, because estimation of VT with graphical approaches depends more heavily on the number of data points included in the regression analysis, and shorter scan duration meant fewer available data points."

Preclinical • CNS Disorders

Exploratory Evaluation of [11C]MPC6827 (clinicaltrials.gov) - P1 | N=17 | Completed | Sponsor: Columbia University | Recruiting ➔ Completed | N=40 ➔ 17 | Trial completion date: Sep 2025 ➔ Jun 2024

Enrollment change • Trial completion • Trial completion date • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders

Biomarkers. (PubMed, Alzheimers Dement) - "Increased [11C]MPC-6827 brain PET uptake with both increasing Aβ and tau depositions longitudinally in AD brains (along with corroborating biodistribution and autoradiography results) clearly demonstrate the role of early MT dysregulations in Aβ and tau-based neurodegeneration processes. These findings highlight the potential of [11C]MPC-6827 PET as a powerful tool for monitoring MT disintegration early-on. Ongoing experiments are exploring translational potential in humans."

Biomarker • Journal • Alzheimer's Disease • CNS Disorders

Developing Topics. (PubMed, Alzheimers Dement) - "Our [11C]MPC-6827 human studies demonstrate (a) safety and feasibility; (b) robust brain uptake; (c) higher brain uptake in cognitively impaired subjects than in controls; (d) a highly positive correlation among PiB, and FTP uptakes; (e) autoradiography results may indicate not possibly of age confounding the imaging data. This study will be the first to image MT destabilization processes in AD. It will create a new understanding of MT-based processes in the neurodegeneration cascade to optimize approaches of AD diagnosis and monitoring."

Journal • CNS Disorders • Aβ42 • CSF Aβ42 • p-tau181

Alzheimer's Imaging Consortium. (PubMed, Alzheimers Dement) - "Increased [11C]MPC-6827 brain PET uptake with both increasing Aß and tau depositions longitudinally in AD brains (along with corroborating biodistribution and autoradiography results) clearly demonstrate the role of early MT dysregulations in Aß and tau-based neurodegeneration processes. These findings highlight the potential of [11C]MPC-6827 PET as a powerful tool for monitoring MT disintegration early-on. Ongoing experiments are exploring translational potential in humans."

Journal • Alzheimer's Disease • CNS Disorders

Exploring microtubule dynamics in Alzheimer's disease: Longitudinal assessment using [11C]MPC-6827 PET imaging in rodent models of Alzheimer's-related pathology. (PubMed, Alzheimers Dement) - "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..."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders

Exploring Microtubule Dynamics in Alzheimer's Disease: Longitudinal Assessment Using [11C]MPC-6827 PET Imaging in APP/PS1 and PS301S Mouse Models (AAIC 2024) - "Increased [ 11 C]MPC-6827 brain PET uptake with both increasing Aβ and tau depositions longitudinally in AD brains (along with corroborating biodistribution and autoradiography results) clearly demonstrate the role of early MT dysregulations in Aβ and tau-based neurodegeneration processes. These findings highlight the potential of [ 11 C]MPC-6827 PET as a powerful tool for monitoring MT disintegration early-on. Ongoing experiments are exploring translational potential in humans."

Preclinical • Alzheimer's Disease • CNS Disorders

PET Imaging of Microtubules in Cognitively Impaired and Normal Older Adults (AAIC 2024) - "Our [ 11 C]MPC-6827 human studies demonstrate (a) safety and feasibility; (b) robust brain uptake; (c) higher brain uptake in cognitively impaired subjects than in controls; (d) a highly positive correlation among PiB, and FTP uptakes; (e) autoradiography results may indicate not possibly of age confounding the imaging data. This study will be the first to image MT destabilization processes in AD. It will create a new understanding of MT-based processes in the neurodegeneration cascade to optimize approaches of AD diagnosis and monitoring."

Clinical • CNS Disorders • p-tau181

Exploring Microtubule Dynamics in Alzheimer's Disease: Longitudinal Assessment Using [11C]MPC-6827 PET Imaging in APP/PS1 and PS301S Mouse Models (AAIC 2024) - "Increased [11C]MPC-6827 brain PET uptake with both increasing Aß and tau depositions longitudinally in AD brains (along with corroborating biodistribution and autoradiography results) clearly demonstrate the role of early MT dysregulations in Aß and tau-based neurodegeneration processes. These findings highlight the potential of [11C]MPC-6827 PET as a powerful tool for monitoring MT disintegration early-on. Ongoing experiments are exploring translational potential in humans."

Preclinical • Alzheimer's Disease • CNS Disorders

Innate immune activation by microtubule destabilizing agents enhances their efficacy in vivo, as predicted by machine learning analyses of human PBMC treated with a large, bioactive compound library (SITC 2023) - "We confirmed in vitro that Verubulin and Taltobulin activate human monocyte-derived dendritic cells, as shown for approved MDAs like Colchicine and Vinblastine. Our results support further study of the benefits of MDAs in combination with immunotherapies, like checkpoint inhibitors, that require strong anti-tumor immune memory. In particular, Taltobulin shows promise as an MDA with both strong tumor cytotoxic effects and durable immune memory generation with minimal toxicity."

Machine learning • Preclinical • Oncology • IL1B

Verubulin (Azixa) Analogues with Increased Saturation: Synthesis, SAR and Encapsulation in Biocompatible Nanocontainers Based on Ca or Mg Cross-Linked Alginate. (PubMed, Pharmaceuticals (Basel)) - "Verubulin is a potent tubulin polymerization inhibitor, binding to colchicine-binding sites. According to fluorescent microscopy data, compounds that showed cytotoxicity in the MTT test disrupt the normal cytoskeleton of the cell in a pattern similar to that for combretastatin A-4. The hit compound (N-(4-methoxyphenyl)-N,2-dimethyl-5,6,7,8-tetrahydroquinazolin-4-amine) was encapsulated in biocompatible nanocontainers based on Ca or Mg cross-linked alginate and it was demonstrated that its cytotoxic activity was preserved after encapsulation."

Journal • Oncology

Exploratory Evaluation of [11C]MPC6827 (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: Columbia University | Trial primary completion date: Sep 2023 ➔ Sep 2024

Trial primary completion date • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders

Preliminary PET Imaging of Microtubule-Based PET Radioligand [C]MPC-6827 in a Nonhuman Primate Model of Alzheimer's Disease. (PubMed, ACS Chem Neurosci) - "Additionally, in vitro autoradiography studies also corroborated PET imaging results. Here, we report the preliminary results of PET imaging with [C]MPC-6827 in four female vervet monkeys with high or low CSF Aβ levels, which have been shown to correlate with the Aβ plaque burden, similar to humans."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Dementia

Dual PET imaging of microtubules and synaptic density in a mouse model of Alzheimer's Disease (AAIC 2023) - "TG APP/PS1 mice demonstrated higher [ 11 C]MPC-6827 and lower [ 18 F]UCB-H brain uptake compared to WT littermates. In vivo PET, ex vivo biodistribution, and in vitro autoradiography data corroborated each other. Preliminary [ 11 C]MPC-6827 and [ 18 F]UCB-H PET evaluations showed negative correlations (* r = -0.778), suggesting MT destabilization and synaptic loss happen concurrently."

Preclinical • Alzheimer's Disease • CNS Disorders

Dual PET imaging of microtubules and synaptic density in a mouse model of Alzheimer's Disease (AAIC 2023) - "TG APP/PS1 mice demonstrated higher [11C]MPC-6827 and lower [18F]UCB-H brain uptake compared to WT littermates. In vivo PET, ex vivo biodistribution, and in vitro autoradiography data corroborated each other. Preliminary [11C]MPC-6827 and [18F]UCB-H PET evaluations showed negative correlations (*r= -0.778), suggesting MT destabilization and synaptic loss happen concurrently."

Preclinical • Alzheimer's Disease • CNS Disorders

Binding Parameters of [C]MPC-6827, a Microtubule-Imaging PET Radiopharmaceutical in Rodents. (PubMed, Pharmaceuticals (Basel)) - "It exhibited ideal binding characteristics (typical of a CNS radiopharmaceutical) including LogP (2.9), K (15.59 nM), and B (11.86 fmol/mg). Most important, [C]MPC-6827 showed high serum and metabolic stability (>95%) in rat plasma and brain samples."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Movement Disorders • Parkinson's Disease • Solid Tumor

FIRST MICROTUBULE-BASED PET IMAGING STUDIES IN COGNITIVELY NORMAL AND IMPAIRED OLDER ADULT SUBJECTS--A PILOT STUDY. (CTAD 2022) - "Our lab reported the first brain-penetrant PET radiotracer [11C]MPC-6827 to image MTs in vivo in both rodent and non-human primate models of AD... Our preliminary results here suggest that MT destabilization precedes paired helical filaments of tau in neurofibrillary tangles. We are currently collecting data on more subjects to exploit the clinical significance of the MT-based PET in AD imaging. All abstracts are embargoed until the day and time of presentation at the CTAD Conference S130"

Clinical • Alzheimer's Disease • CNS Disorders

Antitumor Activity of Tubulin-Binding Agent MPC-6827 on Different Types of Cancer Cell Lines. (PubMed, Cell Mol Biol (Noisy-le-grand)) - "These parameters showed that 4 nM was the optimum concentration for HeLa and A549 cells, while 2 nM was the optimum concentration for MCF-7 cells. The use of optimum concentrations for each cell line has shown that while there was a significant decrease in mitotic index, BrdU labelling index, there was a significant increase in apoptotic index."

Journal • Preclinical • Breast Cancer • Cervical Cancer • Oncology • Solid Tumor

Radiosynthesis and evaluation of [C]AG-488, a dual anti-angiogenetic and anti-tubulin PET ligand. (PubMed, Bioorg Med Chem Lett) - "AG-488 aka FLAG-003 is a novel ligand with established antiangiogenetic properties via activation of receptor thymidine kinase (RTK) and anti-tubulin properties in tumor cells...However, blocking studies with antitubulin and RTK agent HD-800 and microtubule depolymerizing agent MPC-6827 show increased binding of [C]AG-488 in brain. The pattern of tracer binding in blocking conditions is similar to the baseline conditions. The higher binding may be due to the increased plasma uptake of radiotracer or the formation of more free tubulins due to microtubule dynamic instability during the blocking conditions."

Journal • Brain Cancer • Breast Cancer • Glioblastoma • Oncology • Solid Tumor

Preclinical Evaluation of [11C]MPC-6827, a Microtubule PET Tracer in Alzheimer’s Disease Mouse Models (AAIC 2022) - No abstract available

Preclinical • Alzheimer's Disease • CNS Disorders

Preliminary mechanistic insights of a brain-penetrant microtubule imaging PET ligand in a tau-knockout mouse model. (PubMed, EJNMMI Res) - "Collectively, our data indicate that [C]MPC-6827 uptake inversely correlates with MT stability and may better reflect the absence of tau than total tubulin levels. Given the radiotracer binding does not require the presence of aggregated tau, we hypothesize that [C]MPC-6827 may be particularly useful in preclinical stages of AD prior to tau deposition. Our study provides immediate clarity on high uptake of the MT-based radiotracer in AD brains, which directly informs clinical utility in MT/tau-based PET imaging studies."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Dementia • MAPT

Initial Evaluations of the Microtubule-Based PET Radiotracer, [C]MPC-6827 in a Rodent Model of Cocaine Abuse. (PubMed, Front Med (Lausanne)) - "Our initial observations suggest that [C]MPC-6827 uptake decreases in cocaine self-administered rats and that it may selectively bind to destabilized tubulin units in the brain. Further longitudinal studies correlating cocaine intake with [C]MPC-6827 PET brain measures could potentially establish the MT scaffold as an imaging biomarker for CUD, providing researchers and clinicians with a sensitive tool to better understand the biological underpinnings of CUD and tailor new treatments."

Journal • Preclinical • Neuroblastoma • Oncology • Solid Tumor

Preclinical evaluation of a microtubule PET ligand [C]MPC-6827 in tau and amyotrophic lateral sclerosis animal models. (PubMed, Pharmacol Rep) - "Our finding indicates a trend of loss of microtubule binding of [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 [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. Preclinical Evaluation of a Microtubule PET Ligand [C]MPC-6827 in Tau and Amyotrophic Lateral Sclerosis Animal Models. J. S. Dileep Kumar, Andrei Molotkov, Jongho Kim, Patrick Carberry, Sidney Idumonyi, John Castrillon, Karen Duff, Neil A. Shneider, Akiva Mintz."

Journal • Preclinical • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders

Preliminary Evaluations of [C]Verubulin: Implications for Microtubule Imaging With PET. (PubMed, Front Neurosci) - "We also conducted the first comparative in vivo PET imaging study with [C]verubulin, [C]HD-800 and [C]colchicine in a non-human primate. [C]Verubulin and [C]HD-800 require pharmacokinetic modeling and quantification studies to understand the role of how these radiotracers bind to MTs before translation to human use."

Journal • Alzheimer's Disease • CNS Disorders

In vivo evaluation of a microtubule PET ligand, [C]MPC-6827, in mice following chronic alcohol consumption. (PubMed, Pharmacol Rep) - "This pilot study indicates a trend of loss of microtubule binding in whole brain and prefrontal cortex of chronic alcohol administered mice brain compared to control mice, but no loss in heart or liver. These results indicate the potential of [C]MPC-6827 as a PET ligand for further in vivo imaging investigations of AUD in human."

Journal • Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders