PET Radiopharmaceuticals for Alzheimer’s Disease and Parkinson’s Disease Diagnosis, the Current and Future Landscape
Abstract
:1. Introduction
2. PET Imaging Agents for the Diagnosis AD and PD
2.1. PET-Tracers for the Imaging of Aβ Plaques
2.1.1. First Generation of Aβ PET Tracers
Benzothiazole (BTA) Derivatives
The Stilbene and Styrylpyridine Derivatives
2.1.2. Second Generation of Aβ PET Tracers
Benzofuran, Benzoxazole and Imidazobenzothiazole Derivatives
2.1.3. The Clinical Utility and Consequences of Clinically Approved PET-Aβ Radiotracers
2.2. PET-Tracers for the Imaging of Tau Aggregates
2.2.1. First Generation of Tau-PET Tracers
The Arylquinolines
The Phenylbutadienylbenzothiazoles (PBB)
The Carbazole and Benzimidazole Derivatives
2.2.2. Second Generation of Selective Tau Tracers
Optimized First Generation Tau Tracers
The Azaindole-Isoquinoline and Naphthyridine Derivatives
2.3. Selective PET-Tracers for the Imaging of α-syn
2.3.1. The Phenothiazine Derivatives
2.3.2. The Indolinone and Indolinonediene Derivatives
2.3.3. Chalcone Derivatives and Structural Cogeners
2.3.4. Diarybisthiazole Compounds
3. Conclusions
Funding
Conflicts of Interest
References
- Alzheimer’s Disease International. The Global Impact of Dementia: An Analysis of Prevalence, Incidence, Cost and Trends; World Alzheimer Report 2015; Alzheimer’s Disease International: London, UK, 2015. [Google Scholar]
- Alzheimer’s Disease International. World Alzheimer Report 2018—The State of the Art of Dementia Research: New Frontiers; Alzheimer’s Disease International: London, UK, 2018. [Google Scholar]
- World Health Organisation-Alzheimer’s Disease International. Dementia: A Public Health Priority; WHO: Geneva, Switzerland, 2012. [Google Scholar]
- Trevisan, K.; Cristina-Pereira, R.; Silva-Amaral, D.; Aversi-Ferreira, T.A. Theories of Aging and the Prevalence of Alzheimer’s Disease. Biomed. Res. Int. 2019, 1–9. [Google Scholar] [CrossRef] [Green Version]
- ** a Parkinson disease imaging agent. PLoS ONE 2013, 8, e55031. [Google Scholar] [CrossRef] [Green Version]
- Zhang, X.; **, H.; Padakanti, P.K.; Li, J.; Yang, H.; Fan, J.; Mach, R.H.; Kotzbauer, P.; Tu, Z. Radiosynthesis and in Vivo Evaluation of Two PET Radioligands for Imaging α-Synuclein. Appl. Sci. 2014, 4, 66–78. [Google Scholar] [CrossRef] [Green Version]
- Honson, N.S.; Johnson, R.L.; Huang, W.; Inglese, J.; Austin, C.P.; Kuret, J. Differentiating Alzheimer disease-associated aggregates with small molecules. Neurobiol. Dis. 2007, 28, 251–260. [Google Scholar] [CrossRef] [Green Version]
- Chu, W.; Zhou, D.; Gaba, V.; Liu, J.; Li, S.; Peng, X.; Xu, J.; Dhavale, D.; Bagchi, D.P.; d’Avignon, A.; et al. Design, Synthesis, and Characterization of 3-(Benzylidene)indolin-2-one Derivatives as Ligands for α-Synuclein Fibrils. J. Med. Chem. 2015, 58, 6002–6017. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hsieh, C.-J.; Xu, K.; Lee, I.; Graham, T.J.A.; Tu, Z.; Dhavale, D.; Kotzbauer, P.; Mach, R.H. Chalcones and Five-Membered Heterocyclic Isosteres Bind to Alpha Synuclein Fibrils in Vitro. ACS Omega 2018, 3, 4486–4493. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ono, M.; Maya, Y.; Haratake, M.; Ito, K.; Mori, H.; Nakayama, M. Aurones serve as probes of beta-amyloid plaques in Alzheimer’s disease. Biochem. Biophys. Res. Commun. 2007, 361, 116–121. [Google Scholar] [CrossRef] [PubMed]
- Ono, M.; Haratake, M.; Mori, H.; Nakayama, M. Novel chalcones as probes for in vivo imaging of beta-amyloid plaques in Alzheimer’s brains. Bioorg. Med. Chem. 2007, 15, 6802–6809. [Google Scholar] [CrossRef]
- Ono, M.; Yoshida, N.; Ishibashi, K.; Haratake, M.; Arano, Y.; Mori, H.; Nakayama, M. Radioiodinated flavones for in vivo imaging of beta-amyloid plaques in the brain. J. Med. Chem. 2005, 48, 7253–7260. [Google Scholar] [CrossRef]
- Meng, X.; Munishkina, L.A.; Fink, A.L.; Uversky, V.N. Effects of Various Flavonoids on the α-Synuclein Fibrillation Process. Parkinsons. Dis. 2010, 2010, 650794. [Google Scholar] [CrossRef] [Green Version]
- Zhu, M.; Han, S.; Fink, A.L. Oxidized quercetin inhibits α-synuclein fibrillization. Biochim. Biophys. Acta 2013, 1830, 2872–2881. [Google Scholar] [CrossRef]
- Masuda, M.; Suzuki, N.; Taniguchi, S.; Oikawa, T.; Nonaka, T.; Iwatsubo, T.; Hisanaga, S.-i.; Goedert, M.; Hasegawa, M. Small molecule inhibitors of alpha-synuclein filament assembly. Biochemistry 2006, 45, 6085–6094. [Google Scholar] [CrossRef]
- Cui, M.; Ono, M.; Watanabe, H.; Kimura, H.; Liu, B.; Saji, H. Smart near-infrared fluorescence probes with donor-acceptor structure for in vivo detection of β-amyloid deposits. J. Am. Chem. Soc. 2014, 136, 3388–3394. [Google Scholar] [CrossRef]
- Ono, M.; Doi, Y.; Watanabe, H.; Ihara, M.; Ozaki, A.; Saji, H. Structure–activity relationships of radioiodinated diphenyl derivatives with different conjugated double bonds as ligands for α-synuclein aggregates. RSC Adv. 2016, 6, 44305–44312. [Google Scholar] [CrossRef]
- Fanti, S.; Bonfiglioli, R.; Decristoforo, C. Highlights of the 30th Annual Congress of the EANM, Vienna 2017: “Yes we can-make nuclear medicine great again”. Eur. J. Nucl. Med. Mol. Imaging 2018, 45, 1781–1794. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wester, H.-J.; Yousefi, B.H. US20170157274A1-Compounds Binding to Neuropathological Aggregates-Google Patents. Available online: https://patents.google.com/patent/US20170157274A1/en (accessed on 24 December 2019).
Tracer | Log P | Aβ(1-40) fibrils, [nM] | Aβ(1-42) Fibrils, [nM] | Aβ plaques in Brain Homogenates, [nM] | Brain Uptake [%ID/g] (2 min p.i.) | Brain Clearance [%ID/g] (30 min p.i.) | |||
---|---|---|---|---|---|---|---|---|---|
Ki | Kd | Ki | Kd | Ki | Kd | ||||
Th-T [92,96] | 0.57 | 890 580 | NA | NA | NA | NA | NA | NA | NA |
[11C]PiB [91,94] [105,131] | 1.2 2.23 | 4.3 | 4.7 | NA | NA | IC50: 2.3 | 1.4 | 0.21%ID-kg/g 1 1.50 (5 min p.i.) | 0.018%ID-kg/g 1 0.31 |
[18F]Florbetaben [114,119] | 2.41 | NA | NA | NA | NA | 6.7 2.22 | NA | 7.77 | 1.59 |
[18F]Florbetapir [119] | NA | NA | NA | NA | NA | 2.87 | 3.72 | 7.33 | 1.88 (60 min p.i.) |
[18F]Flutemetamol [103,105] | 3.2 2 | 15.3 | 1.6 | NA | NA | NA | NA | 3505 nM | 980 nM |
NA | NA | NA | NA | NA | NA | NA | 3.67 (5 min p.i.) | 0.42 | |
[11C]6-Me-BTA-1 [92,94,96] | 3.36 | 20.2 10 | NA | NA | NA | NA | NA | 7.61 0.223%ID-kg/g 1 | 2.76 0.083%ID-kg/g 1 |
[11C]SB-13 [110,112] | 2.36 | 6.0 | NA | NA | NA | 1.2 | NA | 1.15 (cortex) 1.15 (cerebellum) | 0.42 (cortex) 0.41 (cerebellum) |
[18F]FMAPO [112,114] | 2.95 | NA | NA | NA | NA | 5.0 | NA | 9.75 | 1.70 |
[18F]Flutafuranol [18F]AZD4694 [103] | 2.8 2 | 18.5 | 2.3 | NA | NA | NA | NA | 1550 nM | 154 nM |
[18F]MK-3328 [131] | 2.91 | NA | NA | NA | NA | IC50: 10.5 | NA | NA | NA |
[18F]AD-269 [131] | 3.42 | NA | NA | NA | NA | IC50: 8.0 | NA | NA | NA |
[18F]FIBT [133,134] | 1.92 | 2.1 | NA | NA | NA | NA | 0.7 | ~7.3 3 | ~1.25 3 |
Tracer | Log P | Tau Affinity [nM] | Selectivity tau/Aβ | Aβ Affinity (nM) | Brain Uptake [%ID/g] | Brain Clearance [%ID/g] | |
---|---|---|---|---|---|---|---|
HITP | AD-PHF, Kd [nM] | 2 min p.i. | 30 min p.i. | ||||
BF-158 [155] | 1.67 | EC50: 399 | NA | 1.60 1 | Ki: > 5000 | 11.3 | 3.1 |
BF-170 [155] | 1.85 | EC50: 221 | NA | 3.50 1 | Ki: > 5000 | 9.1 | 0.25 |
[18F]THK-523 [156,157] | 2.40 | Kd1:1.67 Kd2:21.74 Ki: 59.30 | 86.50 | 10 2 | Kd1 (Aβ fibrils): 20.7 | 2.75 | 1.47 |
[18F]THK-5105 [157] | 3.03 | Kd1:1.45 Kd2:7.40 Ki: 7.80 | 2.63 | 25 2 | Kd1 (Aβ fibrils): 35.9 | 9.20 | 3.61 |
[18F]THK-5117 [157] | 2.32 | 10.50 | 5.19 | 30 2 | NA | 6.06 | 0.59 |
[18F]THK-5351 [164] | 1.5 | NA | 2.9 | NA | NA | NA | NA |
[11C]PBB3 [172,173] | 3.3 | NA | Kd: 2.55 3 | 48 2 | Kd: 114 3 | 1.92 (1 min p.i.) | 0.11 |
[18F]Flortaucipir (AV-1451,[18F]T807) [178,191] | 1.67 | NA | 14.6 3 | 25 2 | NA | 4.43 (5 min p.i.)7.5 | 0.620.8 |
[18F]T808 [179,191] | NA | NA | 22 | 27 2 | NA | 4.9 | 0.4 |
Tracer | Log P | Tau affinity [nM] | Selectivity, tau/Aβ | Ki, Aβ fibrils (nM) | Brain Uptake [%ID/g] | Brain Clearance [%ID/g] | |
---|---|---|---|---|---|---|---|
HITP | AD-PHF | 2 min p.i. | 30 min p.i. | ||||
[18F]GTP1 [193] | NA | NA | Kd:10.8 | NA | NA | NA | NA |
[18F]PM-PBB3 (APN-1607) | NA | NA | NA | NA | NA | NA | NA |
(*9) [202] | NA | NA | Ki: 8.8 | >11361 | >10000 | NA | NA |
[18F]MK-6240 [202] | 3.32 | NA | Ki: 0.36 | >277771 | >10000 | NA | NA |
(*12) [202] | 2.90 | NA | Ki: 52.6 | >190 | >10000 | NA | NA |
[18F]RO-948 (RO6958948)[53] [199] | 3.22 | NA | 44% 2 pIC50: 3 8.4 | NA | pIC50: < 6 4 | 5.7 5 | 10.9 6 |
[18F]PI-2620 [53] | NA | NA | pIC50: 8.5 7 | NA | pIC50: < 6 4 | 5.9 5 | 16.6 6 |
[18F]JNJ64349311 (JNJ311) [206] | 2.2 | NA | Ki: 8 8 | >500 | >4398 9 IC50: < 5 9 | 1.9 10 | 0.3 10 |
Tracer | Log D | α-syn Affinity [nM] | Aβ Fibrils Affinity [nM] | Tau Fibrils Affinity [nM] | Brain Uptake [%ID/g] | Brain Clearance [%ID/g] | ||||
---|---|---|---|---|---|---|---|---|---|---|
Ki | Kd | Ki | Kd | Ki | Kd | 5 min p.i. | 60 min p.i. | |||
α-syn Fibrils | Human PD Homogenate | |||||||||
[11C]SIL5 [209,210,211] | 3.79 | 32.1. 66.2. | 83.1 | NA | 110 | NA | 136 | NA | 0.953 | 0.158 |
[125I]SIL23 [209,210] | 5.72 | 57.9 | NA | 148 | NA | 635 | NA | 230 | NA | NA |
[18F]SIL26 [209,210,211] | 4.02 | 49.0 15.5. | 33.5 | NA | 103 | NA | 125 | NA | 0.758 | 0.410 |
*14 [[213] | 4.2 1 | 79.5 | NA | NA | 113.3 | NA | 853.5 | NA | NA | NA |
*20 [213] | 3.5 2 | 40.7 | NA | NA | 27.6 | NA | 53.7 | NA | NA | NA |
[18F]46a [213] | 4.18 | 2.1 | NA | 8.9 | 142.4 | NA | 80.1 | NA | NA | NA |
*11a,b [214] | 3.54 3 | 18.5 | NA | NA | 91.5 | NA | >1000 | NA | NA | NA |
[125I]IDP-4 [222] | NA | NA | NA | 5.4 | NA | 16.24 | NA | NA | 0.45 (2 min p.i.) | 0.42 |
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Uzuegbunam, B.C.; Librizzi, D.; Hooshyar Yousefi, B. PET Radiopharmaceuticals for Alzheimer’s Disease and Parkinson’s Disease Diagnosis, the Current and Future Landscape. Molecules 2020, 25, 977. https://doi.org/10.3390/molecules25040977
Uzuegbunam BC, Librizzi D, Hooshyar Yousefi B. PET Radiopharmaceuticals for Alzheimer’s Disease and Parkinson’s Disease Diagnosis, the Current and Future Landscape. Molecules. 2020; 25(4):977. https://doi.org/10.3390/molecules25040977
Chicago/Turabian StyleUzuegbunam, Bright Chukwunwike, Damiano Librizzi, and Behrooz Hooshyar Yousefi. 2020. "PET Radiopharmaceuticals for Alzheimer’s Disease and Parkinson’s Disease Diagnosis, the Current and Future Landscape" Molecules 25, no. 4: 977. https://doi.org/10.3390/molecules25040977