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Here, we aimed to synthesize a dimer caffeine-indan linked by a 6-carbon chain to cross the blood\u2013brain barrier and tested its ability to bind \u03b1-synuclein, reducing misfolding, behavioral abnormalities, and neurodegeneration in our rodent model. Behavioral tests and histological stains assessed neuroprotective effects of the dimer compound. A rapid synthesis of the 18F-labeled analogue enabled Positron Emission Tomography and Computed Tomography imaging for biodistribution measurement. Molecular docking analysis showed that the dimer binds to \u03b1-synuclein N- and C-termini and the non-amyloid-\u03b2-component (NAC) domain, similar to 1-aminoindan, and this binding promotes a neuroprotective \u03b1-synuclein \u201cloop\u201d conformation. The dimer also binds to the orthosteric binding site for adenosine within the adenosine A1 receptor. Immunohistochemistry and confocal imaging showed the dimer abolished \u03b1-synuclein upregulation and aggregation in the substantia nigra and hippocampus, and the dimer mitigated cognitive deficits, anxiety, despair, and motor abnormalities. The 18F-labeled dimer remained stable post-injection and distributed in various organs, notably in the brain, suggesting its potential as a Positron Emission Tomography tracer for \u03b1-synuclein and adenosine A1 receptor in Parkinson\u2019s disease therapy.<\/jats:p>","DOI":"10.3390\/ijms25179386","type":"journal-article","created":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T11:12:13Z","timestamp":1724929933000},"page":"9386","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The Bifunctional Dimer Caffeine-Indan Attenuates \u03b1-Synuclein Misfolding, Neurodegeneration and Behavioral Deficits after Chronic Stimulation of Adenosine A1 Receptors"],"prefix":"10.3390","volume":"25","author":[{"given":"Elisabet","family":"Jakova","sequence":"first","affiliation":[{"name":"Department of Surgery, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7655-665X","authenticated-orcid":false,"given":"Omozojie P.","family":"Aigbogun","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Saskatchewan, Saskatoon, SK S7N 5C9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2013-1601","authenticated-orcid":false,"given":"Mohamed Taha","family":"Moutaoufik","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Regina, Regina, SK S4S 0A2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin J. H.","family":"Allen","sequence":"additional","affiliation":[{"name":"Pharmaceutical and Nutrition Sciences Research Group, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"},{"name":"College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Omer","family":"Munir","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology, Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Devin","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Saskatchewan, Saskatoon, SK S7N 5C9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4527-7404","authenticated-orcid":false,"given":"Changiz","family":"Taghibiglou","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology, Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohan","family":"Babu","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Regina, Regina, SK S4S 0A2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8392-5268","authenticated-orcid":false,"given":"Chris P.","family":"Phenix","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Saskatchewan, Saskatoon, SK S7N 5C9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ed S.","family":"Krol","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5058-7087","authenticated-orcid":false,"given":"Francisco S.","family":"Cayabyab","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Stockwell, J., Jakova, E., and Cayabyab, F.S. (2017). Adenosine A1 and A2A receptors in the brain: Current research and their role in neurodegeneration. Molecules, 22.","DOI":"10.3390\/molecules22040676"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Chang, C.-P., Wu, K.-C., Lin, C.-Y., and Chern, Y. (2021). Emerging roles of dysregulated adenosine homeostasis in brain disorders with a specific focus on neurodegenerative diseases. J. Biomed. Sci., 28.","DOI":"10.1186\/s12929-021-00766-y"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s40035-022-00284-3","article-title":"Adenosine A1 receptor ligands bind to \u03b1-synuclein: Implications for \u03b1-synuclein misfolding and \u03b1-synucleinopathy in Parkinson\u2019s disease","volume":"11","author":"Jakova","year":"2022","journal-title":"Transl. Neurodegener."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"712","DOI":"10.4103\/1673-5374.266916","article-title":"Long-term adenosine A1 receptor activation-induced sortilin expression promotes \u03b1-synuclein upregulation in dopaminergic neurons","volume":"15","author":"Lv","year":"2020","journal-title":"Neural Regen. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1021\/acschemneuro.5b00172","article-title":"Drugs that bind to \u03b1-synuclein: Neuroprotective or neurotoxic?","volume":"6","author":"Kakish","year":"2015","journal-title":"ACS Chem. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1002\/elps.201600253","article-title":"Behavior of \u03b1-synuclein\u2013drug complexes during nanopore analysis with a superimposed AC field","volume":"38","author":"Jakova","year":"2017","journal-title":"Electrophoresis"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"P6-079","DOI":"10.1212\/WNL.90.15_supplement.P6.079","article-title":"Parkinson Disease from long term drug abuse: Meta-analysis of amphetamine\/methamphetamine and Parkinson Disease (P6. 079)","volume":"90","author":"Tripathi","year":"2018","journal-title":"Neurology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1007\/s12640-019-00149-0","article-title":"How important is the use of cocaine and amphetamines in the development of Parkinson disease? A computational study","volume":"37","author":"Pregeljc","year":"2020","journal-title":"Neurotox. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1007\/s12010-022-04155-5","article-title":"Study of the Effects of Nicotine and Caffeine for the Treatment of Parkinson\u2019s Disease","volume":"195","author":"Biswas","year":"2023","journal-title":"Appl. Biochem. Biotechnol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1021\/acschemneuro.6b00209","article-title":"Novel Dimer Compounds That Bind \u03b1-Synuclein Can Rescue Cell Growth in a Yeast Model Overexpressing \u03b1-Synuclein. A Possible Prevention Strategy for Parkinson\u2019s Disease","volume":"7","author":"Kakish","year":"2016","journal-title":"ACS Chem. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1080\/00498254.2021.1943566","article-title":"Employing in vitro metabolism to guide design of F-labelled PET probes of novel \u03b1-synuclein binding bifunctional compounds","volume":"51","author":"Nwabufo","year":"2021","journal-title":"Xenobiotica"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1016\/j.isci.2019.08.057","article-title":"Rewiring of the human mitochondrial interactome during neuronal reprogramming reveals regulators of the respirasome and neurogenesis","volume":"19","author":"Moutaoufik","year":"2019","journal-title":"iScience"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1016\/j.str.2021.05.002","article-title":"The structural heterogeneity of \u03b1-synuclein is governed by several distinct subpopulations with interconversion times slower than milliseconds","volume":"29","author":"Chen","year":"2021","journal-title":"Structure"},{"key":"ref_14","first-page":"1048","article-title":"Additional simulation data of \u03b1-synuclein monomer","volume":"29","author":"Chen","year":"2021","journal-title":"Dataset"},{"key":"ref_15","first-page":"233","article-title":"Positron emission tomography as a tool for studying alcohol abuse","volume":"31","author":"Thanos","year":"2008","journal-title":"Alcohol Res. Health"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"13873","DOI":"10.1021\/acs.joc.1c01474","article-title":"18F-Fluorination: Challenge and Opportunity for Organic Chemists","volume":"86","author":"Halder","year":"2021","journal-title":"J. Org. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1111\/j.1365-2125.2011.04085.x","article-title":"Positron emission tomography molecular imaging for drug development","volume":"73","author":"Matthews","year":"2012","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1177\/00912700122010357","article-title":"Fundamentals of positron emission tomography and applications in preclinical drug development","volume":"41","author":"Cherry","year":"2001","journal-title":"J. Clin. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.drudis.2021.07.025","article-title":"Positron emission tomographic imaging in drug discovery","volume":"27","author":"Ghosh","year":"2022","journal-title":"Drug Discov. Today"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1007\/s11682-018-9967-0","article-title":"The application of positron emission tomography (PET) imaging in CNS drug development","volume":"13","author":"Suridjan","year":"2019","journal-title":"Brain Imaging Behav."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1007\/s00228-003-0643-x","article-title":"Positron emission tomography microdosing: A new concept with application in tracer and early clinical drug development","volume":"59","author":"Grahnen","year":"2003","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1016\/j.tips.2006.04.004","article-title":"Using positron emission tomography to facilitate CNS drug development","volume":"27","author":"Lee","year":"2006","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1007\/s00259-002-0823-4","article-title":"Drug distribution in man: A positron emission tomography study after oral administration of the labelled neuroprotective drug vinpocetine","volume":"29","author":"Halldin","year":"2002","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Miyoshi, S., Mitsuoka, K., Nishimura, S., and Veltkamp, S.A. (2011). Radioisotopes in drug research and development: Focus on positron emission tomography. Radioisotopes\u2014Applications in Bio-Medical Science, InTech\u2014Open Access Publisher.","DOI":"10.5772\/22728"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Sekar, S., Zhang, Y., Miranzadeh Mahabadi, H., Buettner, B., and Taghibiglou, C. (2023). Low-Field Magnetic Stimulation Alleviates MPTP-Induced Alterations in Motor Function and Dopaminergic Neurons in Male Mice. Int. J. Mol. Sci., 24.","DOI":"10.20944\/preprints202305.0214.v1"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Sekar, S., Viswas, R.S., Miranzadeh Mahabadi, H., Alizadeh, E., Fonge, H., and Taghibiglou, C. (2021). Concussion\/mild traumatic brain injury (TBI) induces brain insulin resistance: A positron emission tomography (PET) scanning study. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22169005"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1021\/cn5002914","article-title":"Rasagiline, a suicide inhibitor of monoamine oxidases, binds reversibly to \u03b1-synuclein","volume":"6","author":"Kakish","year":"2014","journal-title":"ACS Chem. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/s41586-018-0236-6","article-title":"Structure of the adenosine-bound human adenosine A1 receptor\u2013Gi complex","volume":"558","author":"Khoshouei","year":"2018","journal-title":"Nature"},{"key":"ref_29","first-page":"49","article-title":"Molecular modeling of adenosine receptors. I. The ligand binding site on the A1 receptor","volume":"9","author":"Ijzerman","year":"1992","journal-title":"Drug Des. Discov."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Carpenter, B., and Lebon, G. (2017). Human adenosine A2A receptor: Molecular mechanism of ligand binding and activation. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00898"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1080\/00498254.2022.2140315","article-title":"An HPLC-UV validated bioanalytical method for measurement of in vitro Phase 1 kinetics of \u03b1-synuclein binding bifunctional compounds","volume":"52","author":"Aigbogun","year":"2022","journal-title":"Xenobiotica"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1212\/WNL.0b013e318263570d","article-title":"Caffeine for treatment of Parkinson disease","volume":"79","author":"Postuma","year":"2012","journal-title":"Neurology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1212\/WNL.0000000000004568","article-title":"Caffeine as symptomatic treatment for Parkinson disease (Caf\u00e9-PD): A randomized trial","volume":"89","author":"Postuma","year":"2017","journal-title":"Neurology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"S205","DOI":"10.3233\/JAD-2010-091459","article-title":"Effects of caffeine in Parkinson\u2019s disease: From neuroprotection to the management of motor and non-motor symptoms","volume":"20","author":"Prediger","year":"2010","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1002\/ana.10028","article-title":"Cigarette smoking and the incidence of Parkinson\u2019s disease in two prospective studies","volume":"50","author":"Zhang","year":"2001","journal-title":"Ann. Neurol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1093\/aje\/155.8.732","article-title":"Parkinson\u2019s disease risks associated with cigarette smoking, alcohol consumption, and caffeine intake","volume":"155","author":"Checkoway","year":"2002","journal-title":"Am. J. Epidemiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1002\/mds.25028","article-title":"Nicotine as a potential neuroprotective agent for Parkinson\u2019s disease","volume":"27","author":"Quik","year":"2012","journal-title":"Mov. Disord."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"144186","DOI":"10.1016\/j.gene.2019.144186","article-title":"Structural analysis of the effects of mutations in Ubl domain of Parkin leading to Parkinson\u2019s disease","volume":"726","author":"Biswas","year":"2020","journal-title":"Gene"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.jgg.2016.05.005","article-title":"Parkin somatic mutations link melanoma and Parkinson\u2019s disease","volume":"43","author":"Levin","year":"2016","journal-title":"J. Genet. Genom."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.parkreldis.2012.03.010","article-title":"Metformin-inclusive sulfonylurea therapy reduces the risk of Parkinson\u2019s disease occurring with Type 2 diabetes in a Taiwanese population cohort","volume":"18","author":"Wahlqvist","year":"2012","journal-title":"Park. Relat. Disord."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"104593","DOI":"10.1016\/j.phrs.2019.104593","article-title":"Emerging neuroprotective effect of metformin in Parkinson\u2019s disease: A molecular crosstalk","volume":"152","author":"Paudel","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Agostini, F., Masato, A., Bubacco, L., and Bisaglia, M. (2022). Metformin repurposing for Parkinson disease therapy: Opportunities and challenges. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010398"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"26438","DOI":"10.1073\/pnas.2009838117","article-title":"Metformin rescues Parkinson\u2019s disease phenotypes caused by hyperactive mitochondria","volume":"117","author":"Mor","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.bbadis.2009.08.013","article-title":"Mitochondrial dysfunction in Parkinson\u2019s disease","volume":"1802","author":"Winklhofer","year":"2010","journal-title":"Biochim. Biophys. Acta BBA-Mol. Basis Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/nrn1868","article-title":"Expanding insights of mitochondrial dysfunction in Parkinson\u2019s disease","volume":"7","author":"Muqit","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.tibs.2020.11.007","article-title":"Mitochondrial dysfunction and mitophagy in Parkinson\u2019s disease: From mechanism to therapy","volume":"46","author":"Malpartida","year":"2021","journal-title":"Trends Biochem. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Dimpfel, W., and Hoffmann, J. (2011). Effects of rasagiline, its metabolite aminoindan and selegiline on glutamate receptor mediated signalling in the rat hippocampus slice in vitro. BMC Pharmacol., 11.","DOI":"10.1186\/1471-2210-11-2"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.neuint.2010.06.017","article-title":"Rasagiline protects against alpha-synuclein induced sensitivity to oxidative stress in dopaminergic cells","volume":"57","author":"Chau","year":"2010","journal-title":"Neurochem. Int."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1111\/j.1471-4159.2009.06542.x","article-title":"The neuroprotective mechanism of 1-(R)-aminoindan, the major metabolite of the anti-parkinsonian drug rasagiline","volume":"112","author":"Weinreb","year":"2010","journal-title":"J. Neurochem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"C246","DOI":"10.1152\/ajpcell.00269.2018","article-title":"Toxic doses of caffeine are needed to increase skeletal muscle contractility","volume":"316","author":"Neyroud","year":"2019","journal-title":"Am. J. Physiol.-Cell Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1007\/s40279-021-01521-x","article-title":"Effects of Caffeine on Resistance Exercise: A Review of Recent Research","volume":"51","author":"Grgic","year":"2021","journal-title":"Sports Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"31","DOI":"10.22730\/jmls.2021.18.2.31","article-title":"Progressive nicotine poisoning by multiple transdermal nicotine patches","volume":"18","author":"Kang","year":"2021","journal-title":"J. Med. Life Sci."},{"key":"ref_53","first-page":"357","article-title":"Side effects of caffeine","volume":"27","author":"Opielak","year":"2009","journal-title":"Pol. Merkur. Lek. Organ Pol. Tow. Lek."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1093\/ntr\/ntab086","article-title":"Sensory effects of nicotine and tobacco","volume":"24","author":"Carstens","year":"2022","journal-title":"Nicotine Tob. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.1001\/jama.1992.03490190087036","article-title":"Tobacco dependence and the nicotine patch: Clinical guidelines for effective use","volume":"268","author":"Fiore","year":"1992","journal-title":"JAMA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5762","DOI":"10.1007\/s00415-022-11267-9","article-title":"Diagnostic and therapeutic agents that target alpha-synuclein in Parkinson\u2019s disease","volume":"269","author":"Nwabufo","year":"2022","journal-title":"J. Neurol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"81","DOI":"10.2165\/00003088-200241020-00001","article-title":"The impact of efflux transporters in the brain on the development of drugs for CNS disorders","volume":"41","author":"Taylor","year":"2002","journal-title":"Clin. Pharmacokinet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1021\/acschemneuro.6b00029","article-title":"Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery","volume":"7","author":"Wager","year":"2016","journal-title":"ACS Chem. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4568","DOI":"10.1021\/jm400312y","article-title":"Design and selection parameters to accelerate the discovery of novel central nervous system positron emission tomography (PET) ligands and their application in the development of a novel phosphodiesterase 2A PET ligand","volume":"56","author":"Zhang","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"8538","DOI":"10.1021\/acs.jmedchem.7b01050","article-title":"The Discovery of a Novel Phosphodiesterase (PDE) 4B-Preferring Radioligand for Positron Emission Tomography (PET) Imaging","volume":"60","author":"Zhang","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2982","DOI":"10.1021\/acschemneuro.2c00473","article-title":"Synthesis and Evaluation of 18F-Labeled Chalcone Analogue for Detection of \u03b1-Synuclein Aggregates in the Brain Using the Mouse Model","volume":"13","author":"Kaide","year":"2022","journal-title":"ACS Chem. Neurosci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1021\/acschemneuro.0c00801","article-title":"Radiosynthesis, in Vitro and in Vivo Evaluation of [18F]CBD-2115 as a First-in-Class Radiotracer for Imaging 4R-Tauopathies","volume":"12","author":"Lindberg","year":"2021","journal-title":"ACS Chem. Neurosci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1021\/acsmedchemlett.1c00127","article-title":"Leveraging Open Science Drug Development for PET: Preliminary Neuroimaging of 11C-Labeled ALK2 Inhibitors","volume":"12","author":"Murrell","year":"2021","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2247","DOI":"10.1021\/acschemneuro.1c00265","article-title":"Comparing the Pfizer Central Nervous System Multiparameter Optimization Calculator and a BBB Machine Learning Model","volume":"12","author":"Urbina","year":"2021","journal-title":"ACS Chem. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Klann, E.M., Dissanayake, U., Gurrala, A., Farrer, M., Shukla, A.W., Ramirez-Zamora, A., Mai, V., and Vedam-Mai, V. (2022). The Gut\u2013Brain Axis and Its Relation to Parkinson\u2019s Disease: A Review. Front. Aging Neurosci., 13.","DOI":"10.3389\/fnagi.2021.782082"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1038\/s41582-022-00681-2","article-title":"The microbiome\u2013gut\u2013brain axis in Parkinson disease\u2014From basic research to the clinic","volume":"18","author":"Tan","year":"2022","journal-title":"Nat. Rev. Neurol."},{"key":"ref_67","first-page":"2339","article-title":"Exploring the Connection between the Gut Microbiome and Parkinson\u2019s Disease Symptom Progression and Pathology: Implications for Supplementary Treatment Options","volume":"12","author":"Chan","year":"2022","journal-title":"J. Park. Dis."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Nguyen, A.T.N., Tran, Q.L., Baltos, J.-A., McNeill, S.M., Nguyen, D.T.N., and May, L.T. (2023). Small molecule allosteric modulation of the adenosine A1 receptor. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1184360"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1021\/acs.jcim.9b00778","article-title":"Autodock vina adopts more accurate binding poses but autodock4 forms better binding affinity","volume":"60","author":"Nguyen","year":"2019","journal-title":"J. Chem. Inf. Model."},{"key":"ref_70","first-page":"939","article-title":"Allosteric enhancement of adenosine A1 receptor binding and function by 2-amino-3-benzoylthiophenes","volume":"38","author":"Bruns","year":"1990","journal-title":"Mol. Pharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"6165","DOI":"10.1021\/jm800557d","article-title":"2-aminothienopyridazines as novel adenosine A1 receptor allosteric modulators and antagonists","volume":"51","author":"Ferguson","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"9621","DOI":"10.1523\/JNEUROSCI.3991-13.2014","article-title":"Prolonged Adenosine A1 Receptor Activation in Hypoxia and Pial Vessel Disruption Focal Cortical Ischemia Facilitates Clathrin-Mediated AMPA Receptor Endocytosis and Long-Lasting Synaptic Inhibition in Rat Hippocampal CA3-CA1 Synapses: Differential Regulat","volume":"34","author":"Chen","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.brainresbull.2008.03.005","article-title":"Antidepressive-like effects of rapamycin in animal models: Implications for mTOR inhibition as a new target for treatment of affective disorders","volume":"76","author":"Cleary","year":"2008","journal-title":"Brain Res. Bull."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.vascn.2009.03.003","article-title":"A possible utilization of the mice forced swim test for modeling manic-like increase in vigor and goal-directed behavior","volume":"59","author":"Einat","year":"2009","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1016\/j.apsb.2021.08.029","article-title":"Discovery and development of brain-penetrant 18F-labeled radioligands for neuroimaging of the sigma-2 receptors","volume":"12","author":"Zhang","year":"2022","journal-title":"Acta Pharm. Sin. B"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/17\/9386\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:45:10Z","timestamp":1760111110000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/17\/9386"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,29]]},"references-count":75,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["ijms25179386"],"URL":"https:\/\/doi.org\/10.3390\/ijms25179386","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,29]]}}}