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Binding Parameters of [11C]MPC-6827, a Microtubule-Imaging PET Radiopharmaceutical in Rodents
Avinash H Bansode1, Bhuvanachandra Bhoopal1, Krishna Kumar Gollapelli1
1Department of Radiology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA.
Abstract:
Impairment and/or destabilization of neuronal microtubules (MTs) resulting from hyper-phosphorylation of the tau proteins is implicated in many pathologies, including Alzheimer's disease (AD), Parkinson's disease and other neurological disorders. Increasing scientific evidence indicates that MT-stabilizing agents protect against the deleterious effects of neurodegeneration in treating AD. To quantify these protective benefits, we developed the first brain-penetrant PET radiopharmaceutical, [11C]MPC-6827, for in vivo quantification of MTs in rodent and nonhuman primate models of AD. Mechanistic insights revealed from recently reported studies confirm the radiopharmaceutical's high selectivity for destabilized MTs. To further translate it to clinical settings, its metabolic stability and pharmacokinetic parameters must be determined. Here, we report in vivo plasma and brain metabolism studies establishing the radiopharmaceutical-binding constants of [11C]MPC-6827. Binding constants were extrapolated from autoradiography experiments; pretreatment with a nonradioactive MPC-6827 decreased the brain uptake >70%. It exhibited ideal binding characteristics (typical of a CNS radiopharmaceutical) including LogP (2.9), Kd (15.59 nM), and Bmax (11.86 fmol/mg). Most important, [11C]MPC-6827 showed high serum and metabolic stability (>95%) in rat plasma and brain samples.
Insights
Researchers developed a novel PET tracer, [¹¹C]MPC-6827, to measure neuronal microtubules in the brain. This tracer shows high stability and ideal binding characteristics for potential use in Alzheimer's disease research.
Area of Science:
- Neuroscience
- Radiopharmaceutical Chemistry
- Molecular Imaging
Background:
- Neuronal microtubule (MT) destabilization due to tau hyperphosphorylation is linked to neurodegenerative diseases like Alzheimer's disease (AD).
- MT-stabilizing agents show promise in protecting against neurodegeneration in AD.
- Quantifying MTs in vivo is crucial for evaluating therapeutic benefits.
Purpose of the Study:
- To develop and characterize a brain-penetrant PET radiopharmaceutical, [¹¹C]MPC-6827, for in vivo quantification of neuronal microtubules in AD models.
- To assess the metabolic stability and pharmacokinetic parameters of [¹¹C]MPC-6827 for clinical translation.
Main Methods:
- Development of [¹¹C]MPC-6827, a novel PET radiopharmaceutical targeting neuronal MTs.
- In vivo studies in rodent and nonhuman primate models of AD to quantify MTs.
- Plasma and brain metabolism studies, including autoradiography and binding constant determination.
Main Results:
- [¹¹C]MPC-6827 demonstrated high selectivity for destabilized MTs.
- Pretreatment with nonradioactive MPC-6827 reduced brain uptake by over 70%.
- The radiopharmaceutical exhibited favorable binding characteristics (LogP=2.9, Kd=15.59 nM, Bmax=11.86 fmol/mg) and high metabolic stability (>95%) in rat plasma and brain.
Conclusions:
- [¹¹C]MPC-6827 is a promising brain-penetrant PET tracer for in vivo quantification of neuronal microtubules.
- Its established binding constants and high metabolic stability support its potential for clinical application in neurodegenerative disease research.
- This tool can aid in evaluating the efficacy of MT-stabilizing therapies for conditions like Alzheimer's disease.
