Discovery of [¹¹C]MODAG-005, a novel PET tracer targeting alpha-synuclein aggregates

 

Ziel/Aim PET imaging of alpha-synuclein (αSYN) aggregates would be a game changer for facilitating the diagnosis of synucleinopathies and the development of novel therapies. We previously demonstrated that the structural modification of anle138b, an investigational therapeutic for synucleinopathies [1], led to radiotracer candidates with high-affinity binding to αSYN [2] [3]. Here, we report the preclinical evaluation of MODAG-005 as a promising αSYN PET tracer.

Methodik/Methods In vitro binding of [³H]MODAG-005 was determined using human recombinant αSYN, amyloid-beta_1-42 (Aβ), and tau fibrils. (Micro)autoradiography was performed in postmortem human brain tissues from multiple system atrophy (MSA), Parkinson’s disease, Alzheimer’s disease, progressive supranuclear palsy, healthy controls, and in a transgenic αSYN(A30P) mouse model. The binding affinity to αSYN was determined in MSA tissues, and blocking with anle138b was performed. Pharmacokinetics and metabolism of [¹¹C]MODAG-005 were studied in healthy mice, rats and NHP; in vivo target binding was investigated in rats intrastriatal injected with αSYN fibrils (n=4).

Ergebnisse/Results Saturation binding assays revealed K_d values for [³H]MODAG-005 of 0.2 nM for αSYN, 7 nM for tau, and 21 nM for Aβ fibrils. Autoradiography in human brain tissues confirmed the binding of [³H]MODAG-005 to αSYN with a K_d of 0.25 nM in MSA while showing a specific binding in the αSYN(A30P) mouse model. We show the target engagement of the drug candidate anle138b (K_i=25 nM). The tracer showed excellent blood-brain barrier penetration and fast brain clearance. We detected one metabolite in the brain, with 79% of the parent compound remaining 15 minutes post-injection. Increased tracer binding was detected in the fibril-injected striatum compared to the sham-injected striatum.

Schlussfolgerungen/Conclusions Here, we present a novel PET tracer targeting αSYN in the human brain, with a very high affinity to αSYN aggregates in MSA tissues. Despite the lack of full selectivity, MODAG-005 is one of the most promising αSYN-targeting tracers.

Publication History

Article published online:
30 March 2023

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• Literatur/References

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• 3 Kuebler L.. et al. Eur J Nucl Med Mol Imaging 2021; 48 (06) 1759-1772
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