[11C]MODAG 005 – a novel PET tracer targeting alpha-synuclein aggregates in the brain

Abstract

Synucleinopathies are neurodegenerative diseases characterized by the presence of brain inclusions containing the pathologically aggregated protein α-synuclein (αSYN). The development of a positron emission tomography tracer to detect aggregates of misfolded αSYN would revolutionize disease monitoring and the evaluation of therapeutic efficacy. Here we present the development and preclinical in vitro and in vivo validation of [11C]MODAG-005. In vitro binding experiments demonstrate subnanomolar binding affinity to recombinant αSYN fibrils as well as to αSYN inclusions in human brain tissue. Specific binding in multiple system atrophy brain tissue was detected using autoradiography and microautoradiography, and was validated through immunostaining. In vivo, [11C]MODAG-005 shows good brain penetration, rapid clearance from brain tissue and low metabolite formation in rodents and non-human primates. In addition, a pronounced binding and a good signal-to-noise ratio were achieved in an αSYN fibril-injected rat model and in an αSYN(A30P) transgenic mouse model in correlation to the pathological load. To validate its value for therapy development, we show target engagement of the drug candidate anle138b in the brain tissues from αSYN(A30P) mouse and multiple system atrophy as well as in vivo in αSYN fibril-injected rats. Finally, our translational approach in a first-in-human patient with clinically established MSA, revealed a marked tracer binding in regions affected by αSYN pathology, particularly in the striatum, where the pattern corresponded with the neurodegeneration shown by dopamine transporter single-photon emission computed tomography.

Advancing Parkinson’s Disease Diagnostics: The Potential of Arylpyrazolethiazole Derivatives for Imaging α-Synuclein Aggregates

“…In summary, according to the data described above, general SAR conclusions are available for further optimization of binding affinity and selectivity on α-syn: for ring A, the substitution with an N -monomethylaniline, as it is also seen in the recently published MODAG-005, 13 is better than the N , N -dimenthylaniline and 1,3-dioxole; for ring B, the presence of the pyrazole ring is required; for ring C, 4-bromo substituted thiazole favors binding to α-syn.…”

“…However, the absence of a quantitative kinetic and metabolic analysis of [ 18 F]­F0502B limits its current understanding. Furthermore, [ 11 C]­MODAG-005 has recently been published, but to date it has only been evaluated on one patient …”

“…Furthermore, [ 11 C]MODAG-005 has recently been published, but to date it has only been evaluated on one patient. 13 …”