Design, synthesis, and in vitro evaluation of quinolinyl analogues for α-synuclein aggregation

Yue, Xuyi; Li, Junfeng; Luo, Zonghua; Liu, Jialu; Yang, Hao; Mach, Robert H.; Kotzbauer, Paul T.; Dhavale, Dhruva

doi:10.1016/j.bmcl.2018.02.031

Cited by 15 publications

(17 citation statements)

References 32 publications

(40 reference statements)

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“…After tritiation, [ 3 H]MODAG-001 was tested in saturation binding experiments against human recombinant fibrils and showed very high affinity to αSYN fibrils, with a K d value of 0.6 nM in vitro. Compared to [ 3 H]MODAG-001, all the compounds, which have been described in the literature as potential αSYN PET ligands, showed an at least one order of magnitude lower binding affinity (higher K d values) in vitro towards recombinant αSYN fibrils [ 14 , 21 , 24 – 31 ]. These compounds comprise [ 125 I]SIL23, ( K d = 148 nM) and its derivative SIL26 ( K i = 15.5 nM), [ 24 ] [ 18 F]BF-227 ( K d = 9.6 nM) [ 26 ], several fluorescent probes ( K d s in the micromolar and elevated nanomolar range) [ 32 , 33 ], and the 18 F-labeled 3-(benzylidine)indolin-2-one derivative [ 18 F]46a ( K d = 8.9 nM) [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

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[11C]MODAG-001—towards a PET tracer targeting α-synuclein aggregates

Kuebler

Buss

Leonov

et al. 2020

Eur J Nucl Med Mol Imaging

102

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Purpose Deposition of misfolded alpha-synuclein (αSYN) aggregates in the human brain is one of the major hallmarks of synucleinopathies. However, a target-specific tracer to detect pathological aggregates of αSYN 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. Methods Specificity and selectivity of [3H]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 αSYN fibrils and using in vitro autoradiography in human brain sections of Lewy body dementia (LBD) cases provided by the Neurobiobank Munich (NBM). Results [3H]MODAG-001 revealed a very high affinity towards pure αSYN fibrils (Kd = 0.6 ± 0.1 nM) and only a moderate affinity to hTau46 fibrils (Kd = 19 ± 6.4 nM) as well as amyloid-β1–42 fibrils (Kd = 20 ± 10 nM). [11C]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. (d3)-[11C]MODAG-001 binding was confirmed in fibril-inoculated rat striata using in vivo PET imaging. In vitro autoradiography showed no detectable binding to aggregated αSYN in human brain sections of LBD cases, most likely, because of the low abundance of aggregated αSYN against background protein. Conclusion 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.

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Section: Discussionmentioning

confidence: 99%

“…Over the past years, several attempts have been made to develop an αSYN-specific PET tracer [ 14 , 21 , 24 – 31 ]. However, the low abundance of αSYN inclusions and high similarity to structurally related proteins present in pathological brain regions [ 51 , 55 ] made its discovery very challenging.…”

Section: Discussionmentioning

confidence: 99%

[11C]MODAG-001—towards a PET tracer targeting α-synuclein aggregates

Kuebler

Buss

Leonov

et al. 2020

Eur J Nucl Med Mol Imaging

102

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“…Several compounds containing a quinolinyl moiety and six-membered aromatic rings linked either by a double bond or an oxadiazole bridge were designed by Yue et al for α-syn imaging [ 134 ]. A rational design approach was applied based on previous findings combining key features of the compounds LDS 798 and 2,6-ANS ( Figure 5 ).…”

Section: Alpha-synuclein Pet Tracer Development—from a Molecular Development Point Of Viewmentioning

confidence: 99%

“…Using recombinant α-syn fibrils and brain AD tissue homogenates, the affinity of these compounds was determined to be 21, 79, 18 nM for [ 11 C]52 , [ 18 F]53 , [ 18 F]54 , respectively. Affinity toward Aβ fibrils was determined to be in the same order of magnitude [ 134 ]. These binding characteristics discouraged the authors from further evaluating the compounds in vivo.…”

Section: Alpha-synuclein Pet Tracer Development—from a Molecular Development Point Of Viewmentioning

confidence: 99%

Alpha-Synuclein PET Tracer Development—An Overview about Current Efforts

et al. 2021

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Neurodegenerative diseases such as Parkinson’s disease (PD) are manifested by inclusion bodies of alpha-synuclein (α-syn) also called α-synucleinopathies. Detection of these inclusions is thus far only possible by histological examination of postmortem brain tissue. The possibility of non-invasively detecting α-syn will therefore provide valuable insights into the disease progression of α-synucleinopathies. In particular, α-syn imaging can quantify changes in monomeric, oligomeric, and fibrillic α-syn over time and improve early diagnosis of various α-synucleinopathies or monitor treatment progress. Positron emission tomography (PET) is a non-invasive in vivo imaging technique that can quantify target expression and drug occupancies when a suitable tracer exists. As such, novel α-syn PET tracers are highly sought after. The development of an α-syn PET tracer faces several challenges. For example, the low abundance of α-syn within the brain necessitates the development of a high-affinity ligand. Moreover, α-syn depositions are, in contrast to amyloid proteins, predominantly localized intracellularly, limiting their accessibility. Furthermore, another challenge is the ligand selectivity over structurally similar amyloids such as amyloid-beta or tau, which are often co-localized with α-syn pathology. The lack of a defined crystal structure of α-syn has also hindered rational drug and tracer design efforts. Our objective for this review is to provide a comprehensive overview of current efforts in the development of selective α-syn PET tracers.

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“…Comprehensive and vivid literature is available that highlight the therapeutic value of this pyridine derivative [ 10 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Notably, Gilani et al showed that isonicotinic acid-derived 1,3,4-oxadiazoles exhibited an interesting profile of anti-inflammatory activity, which was superior to the standard drug Naproxen [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Highly Potent Anti-Inflammatory Compounds (ROS Inhibitors) from Isonicotinic Acid

et al. 2021

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In search of anti-inflammatory compounds, novel scaffolds containing isonicotinoyl motif were synthesized via an efficient strategy. The compounds were screened for their in vitro anti-inflammatory activity. Remarkably high activities were observed for isonicotinates 5–6 and 8a–8b. The compound 5 exhibits an exceptional IC50 value (1.42 ± 0.1 µg/mL) with 95.9% inhibition at 25 µg/mL, which is eight folds better than the standard drug ibuprofen (11.2 ± 1.9 µg/mL). To gain an insight into the mode of action of anti-inflammatory compounds, molecular docking studies were also performed. Decisively, further development and fine tuning of these isonicotinates based scaffolds for the treatment of various aberrations is still a wide-open field of research.

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Design, synthesis, and in vitro evaluation of quinolinyl analogues for α-synuclein aggregation

Cited by 15 publications

References 32 publications

[11C]MODAG-001—towards a PET tracer targeting α-synuclein aggregates

[11C]MODAG-001—towards a PET tracer targeting α-synuclein aggregates

Alpha-Synuclein PET Tracer Development—An Overview about Current Efforts

Synthesis of Highly Potent Anti-Inflammatory Compounds (ROS Inhibitors) from Isonicotinic Acid

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