Update on PET Tracer Development for Muscarinic Acetylcholine Receptors
Abstract
:1. Introduction
1.1. Muscarinic Acetylcholine Receptors
1.2. The Role of PET in Diagnosis and Therapeutic Drug Development
1.3. Designing Small Molecules as PET Tracers for the CNS
1.4. Involvement of Computational Approaches in PET Tracer Design
2. Development of PET Tracers for mAChRs
2.1. Development of mAChR Ligands
2.2. PET Tracer Development for In Vivo Muscarinic Imaging of the CNS
2.3. PET Tracer Development for In Vivo Muscarinic Imaging of the PNS
3. Conclusions and Perspective
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Design Criteria | Test Criteria |
---|---|
|
|
Compound | Binding Site | M1 | M2 | M3 | M4 | M5 | lit. |
---|---|---|---|---|---|---|---|
Scopolamine | orthosteric | 1.1 | 2.0 | 0.44 | 0.8 | 2.07 | [55] |
BQCA | allosteric | 845 | >100,000 | >100,000 | >100,000 | >100,000 | [59] |
Trivial Name | Systematic Name | M1 | M2 | M3 | M4 | M5 | Method |
---|---|---|---|---|---|---|---|
(R,S)-IQNB | (R)-quinuclidin-3-yl (S)-2-hydroxy-2-(4-iodophenyl)-2-phenylacetate | 0.49 | - | 1.27 | - | - | KD on transfected A9 L cell membranes using (R,S)-[125I]IQNB [112] |
QNB | quinuclidin-3-yl 2-hydroxy-2,2-diphenylacetate | 0.044 | 0.030 | 0.080 | 0.037 | 0.065 | KD on transfected CHO-K1 cell membranes using [3H]QNB [113] |
scopolamine | (1R,2R,4S,5S,7s)-9-Methyl-3-oxa-9-azatricyclo[3.3.1.02,4]non-7-yl (2S)-3-hydroxy-2-phenylpropanoate | 7.5 | 9.5 | 6.5 | 36.9 | 17.6 | Ki on transfected CHO-K1 cell membranes using [3H]NMS [114] |
benztropine | (1R,3r,5S)-3-(benzhydryloxy)-8-methyl-8-azabicyclo[3.2.1]octane | 6.8 | 14.1 | 11.2 | 22.9 | 4.6 | Ki on transfected Sf9 cell membranes using [3H]NMS [115] |
TRB | (1R,3r,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl 2-hydroxy-2,2-diphenylacetate | 0.7, subtypes were not discriminated | IC50 by [3H]QNB competitive binding on mouse brain homogenates [116] | ||||
NMPB | 1-methylpiperidin-4-yl 2-hydroxy-2,2-diphenylacetate | 0.41, subtypes were not discriminated | KD on mouse cortex [117] | ||||
4-FDEX | (S)-1’-(4-fluorobenzyl)-3-phenyl-[3,4’-bipiperidine]-2,6-dione | 98, subtypes were not discriminated | IC50 by [3H]NMS competitive binding on rat brain homogenates [118] | ||||
xanomeline | 3-[4-(hexyloxy)-1,2,5-thiadiazol-3-yl]-1,2,5,6-tetrahydro-1-methylpyridine oxalate | 7.9 | 8.1 | 7.8 | 11.2 | 9.3 | Ki on transfected CHO-K1 cell membranes using [3H]NMS [119] |
FP-TZTP | 3-(3-fluoropropylsulfanyl)-4-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)-1,2,5-thiadiazole | 7.4 | 2.2 | 79.7 | - | - | Ki on different tissues with different radioligands [106] |
(+)-3-MPB | 1-methylpiperidin-3-yl 2-hydroxy-2,2-diphenylacetate | 1.7 no significant selectivity | Ki on rat neocortex with [3H]QNB. No significant subtype selectivity was observed on transfected CHO-K1 cell membranes using a direct radioligand binding assay [120]. | ||||
GSK1034702 | 4-fluoro-6-methyl-1-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one | 7.9 | >790 | >790 | >790 | >790 | EC50 of FLIPR assay of stably transfected CHO cells [88] |
AF150(S) | 2-methyl-8-methyl-1-thia-3,8-diazaspiro[4.5]dec-2-ene | 390 | 22,000 | - | - | - | Ki on rat cerebral cortex using [3H]pirenzepine (M1) or rat cerebellum using [3H]QNB (M2) [121]. |
- | (S,R)-1-methylpiperidin-3-yl 2-cyclopentyl-2-hydroxy-2-phenylacetate | 3.5 | - | - | - | - | Ki of “high affinity human mAChR M1 assay”. A degree of M1 selectivity was evident from partial blocking of the radioligand with pirenzepine in autoradiography using human brain slices [94]. |
LSN3172176 | ethyl 4-(6-methyl-2-oxoindolin-1-yl)-[1,4’-bipiperidine]-1’-carboxylate | 8.9 | 63.8 | 3031 | 41.4 | 55.6 | Ki on transfected CHO-K1 cell membranes using [3H]NMS [89]. |
M4R-1023 | 5-amino-N-(2,3-difluoro-4-methoxybenzyl)-3,4-dimethylthieno[2,3-c]pyridazine-6-carboxamide | 43.4 | >104 | >104 | >104 | >104 | EC50 of calcium release assay on stably transfected CHO cells [97]. |
MK-6884 | 6-(2-methyl-3-oxoisoindolin-5-yl)-5-(1-((1-methylcyclopentyl)methyl)-1H-pyrazol-4-yl)picolinonitrile | - | - | - | 0.19 | - | Ki on transfected CHO-K1 cell membranes using a tritiated compound of similar chemotype [99] |
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Ozenil, M.; Aronow, J.; Millard, M.; Langer, T.; Wadsak, W.; Hacker, M.; Pichler, V. Update on PET Tracer Development for Muscarinic Acetylcholine Receptors. Pharmaceuticals 2021, 14, 530. https://doi.org/10.3390/ph14060530
Ozenil M, Aronow J, Millard M, Langer T, Wadsak W, Hacker M, Pichler V. Update on PET Tracer Development for Muscarinic Acetylcholine Receptors. Pharmaceuticals. 2021; 14(6):530. https://doi.org/10.3390/ph14060530
Chicago/Turabian StyleOzenil, Marius, Jonas Aronow, Marlon Millard, Thierry Langer, Wolfgang Wadsak, Marcus Hacker, and Verena Pichler. 2021. "Update on PET Tracer Development for Muscarinic Acetylcholine Receptors" Pharmaceuticals 14, no. 6: 530. https://doi.org/10.3390/ph14060530