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POSITRON EMISSION TOMOGRAPHY IMAGING OF ALPHA-SYNUCLEIN AGGREGATION PATHOLOGY: IN VITRO AND IN VIVO EVALUATION OF MODAG-005
Abstract
Aims
Currently, there is no established molecular biomarker available for the non-invasive diagnosis of synucleinopathies. Furthermore, monitoring of progression of synuclein pathology over time and the effect of disease-modifying therapies is urgently needed. Here, we evaluate the potential of MODAG-005 to serve as an alpha-synuclein (αSyn) radiotracer for positron emission tomography (PET) in vitro and in vivo.
Methods
In vitro binding of [3H]MODAG-005 was determined using human recombinant αSyn, tau, and amyloid-beta1-42 (Aβ) fibrils. (Micro)autoradiography was performed in post-mortem human brain tissue from multiple system atrophy, Parkinson’s disease, progressive supranuclear palsy, Alzheimer’s disease, healthy controls, and in the transgenic αSyn(A30P) mouse model. In vivo pharmacokinetics and metabolism of [11C]MODAG-005 were studied in healthy mice and rats, as well as in rats inoculated with αSyn fibrils into the striatum.
Results
In vitro, MODAG-005 shows a high affinity to and a high selectivity for aggregated αSyn (Kd = 0.2 nM vs. 7 nM for tau and >100 nM for Aβ, respectively). This was confirmed in (micro)autoradiography on human brain tissue and in the αSyn(A30P) mouse model, as MODAG-005 binds specifically to αSyn deposits. In vivo, MODAG-005 shows an excellent brain uptake (SUV ~ 2), as well as a fast wash-out (t1/2 = 9min) and only negligible metabolite formation in the brain. Rats inoculated with αSyn fibrils show a well-detectable binding at the injection side.
Conclusions
MODAG-005 holds promise to serve as an αSyn PET tracer as it meets prevailing criteria in established in vitro and in vivo assays and, thus, qualifies for further (pre-)clinical development.