Evaluation of the α-synuclein PET radiotracer (d3)-[11C]MODAG-001 in pigs

The Mechanisms of the Roles of α-Synuclein, Amyloid-β, and Tau Protein in the Lewy Body Diseases: Pathogenesis, Early Detection, and Therapeutics

“…Kaide et al reported that 125 I-PHNP-3, which is one of the chalcone analogs with a 4-(dimethylamino) phenyl group, exhibited a high binding affinity for αSyn against Aβ aggregates in human brain samples [ 42 ]. The MODAG-001 is another promising lead structure to detect αSyn in LBD patients, which demonstrated high brain uptake and favorable in vivo kinetics and biodistribution [ 43 , 44 ].…”

A promising PET tracer candidate targeting α‐synuclein inclusions

“…However, no radiotracers have been approved for clinical use in humans. 5 , 6 That is because the density of α‐synuclein aggregates in PD brains is lower than that of amyloid‐β (Aβ) and Tau in the brains of Alzheimer's disease (AD) patients. Thus, developing specific PET tracers for α‐synuclein is much more challenging.…”

One-Pot Radiosynthesis of [18F]Anle138b—5-(3-Bromophenyl)-3-(6-[18F]fluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrazole—A Potential PET Radiotracer Targeting α-Synuclein Aggregates

“…PET imaging in mice showed excellent brain uptake but detected the formation of two brain-penetrating radio-metabolites—something that hampers quantification of [ 11 C]MODAG-001 uptake. To inhibit the metabolic demethylation process, a deuterated derivative ( d 3)-[ 11 C]MODAG-001 was developed and was shown to be able to bind to pre-formed α-syn fibrils (α-PFF) in a protein deposition rat model [ 25 ]. However, no evidence of binding to aggregated α-syn was observed in human brain sections from DLB patients.…”

“…However, no evidence of binding to aggregated α-syn was observed in human brain sections from DLB patients. Further evaluation of ( d 3)-[ 11 C]MODAG-001 in a porcine brain with intracerebral injection of α-PFF and post-mortem human AD revealed that the radiotracer was not very selective for α-syn and exhibited significant binding in the AD regions [ 25 ].…”

“…Despite mixed results of anle138b/MODAG development when it came to carbon-11 labelling [ 24 , 25 ], we considered it worthwhile to attempt synthesis of a radiotracer based on the original structure of anle138b but labelled with longer-lived fluorine-18 isotope (T 1/2 110 min) which displays excellent decay characteristics for PET imaging (97% β+ decay, 635 keV positron energy). The structure–activity (SAR) studies revealed that the placement of bromine in meta -position of the 5-phenyl ring led to the highest inhibitory activity of anle138b, whereas further modification of that part of the molecule may result in reduced inhibition [ 18 ].…”