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However, a target-specific tracer to detect pathological aggregates of \u03b1SYN remains lacking. Here, we report the development of a positron emission tomography (PET) tracer based on anle138b, a compound shown to have therapeutic activity in animal models of neurodegenerative diseases.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Specificity and selectivity of [<jats:sup>3<\/jats:sup>H]MODAG-001 were tested in in vitro binding assays using recombinant fibrils. After carbon-11 radiolabeling, the pharmacokinetic and metabolic profile was determined in mice. Specific binding was quantified in rats, inoculated with \u03b1SYN fibrils and using in vitro autoradiography in human brain sections of Lewy body dementia (LBD) cases provided by the Neurobiobank Munich (NBM).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>[<jats:sup>3<\/jats:sup>H]MODAG-001 revealed a very high affinity towards pure \u03b1SYN fibrils (<jats:italic>K<\/jats:italic><jats:sub>d<\/jats:sub>\u2009=\u20090.6\u2009\u00b1\u20090.1\u00a0nM) and only a moderate affinity to hTau46 fibrils (<jats:italic>K<\/jats:italic><jats:sub>d<\/jats:sub>\u2009=\u200919\u2009\u00b1\u20096.4\u00a0nM) as well as amyloid-\u03b2<jats:sub>1\u201342<\/jats:sub> fibrils (<jats:italic>K<\/jats:italic><jats:sub>d<\/jats:sub>\u2009=\u200920\u2009\u00b1\u200910\u00a0nM). [<jats:sup>11<\/jats:sup>C]MODAG-001 showed an excellent ability to penetrate the mouse brain. Metabolic degradation was present, but the stability of the parent compound improved after selective deuteration of the precursor. (d<jats:sub>3<\/jats:sub>)-[<jats:sup>11<\/jats:sup>C]MODAG-001 binding was confirmed in fibril-inoculated rat striata using in vivo PET imaging. In vitro autoradiography showed no detectable binding to aggregated \u03b1SYN in human brain sections of LBD cases, most likely, because of the low abundance of aggregated \u03b1SYN against background protein.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>MODAG-001 provides a promising lead structure for future compound development as it combines a high affinity and good selectivity in fibril-binding assays with suitable pharmacokinetics and biodistribution properties.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00259-020-05133-x","type":"journal-article","created":{"date-parts":[[2020,12,28]],"date-time":"2020-12-28T07:02:42Z","timestamp":1609138962000},"page":"1759-1772","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":92,"title":["[11C]MODAG-001\u2014towards a PET tracer targeting \u03b1-synuclein aggregates"],"prefix":"10.1007","volume":"48","author":[{"given":"Laura","family":"Kuebler","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Buss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei","family":"Leonov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergey","family":"Ryazanov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Maurer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Weckbecker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M.","family":"Landau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thea P.","family":"Lillethorup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Bleher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran Sing","family":"Saw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd J.","family":"Pichler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Griesinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armin","family":"Giese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Herfert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,12,28]]},"reference":[{"issue":"6645","key":"5133_CR1","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1038\/42166.","volume":"388","author":"MG Spillantini","year":"1997","unstructured":"Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. 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