Pharmacokinetic evaluation of new drugs using a multi-labelling approach and PET imaging: application to a drug candidate with potential application in neuromuscular disorders

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dc.contributor.authorPassannante, Rossana
dc.contributor.authorGómez Vallejo, Vanessa
dc.contributor.authorSagartzazu Aizpurua, Maialen
dc.contributor.authorVignau Arsuaga, Laura
dc.contributor.authorMarco Moreno, Pablo
dc.contributor.authorAldanondo Aristizabal, Garazi
dc.contributor.authorVallejo Illarramendi, Ainara
dc.contributor.authorAguiar Fernández, Pablo
dc.contributor.authorCossío, Unai
dc.contributor.authorMartín, Abraham
dc.contributor.authorBergare, Jonas
dc.contributor.authorKingston, Lee
dc.contributor.authorElmore, Charles S.
dc.contributor.authorMorcillo Alonso, Miguel Ángel
dc.contributor.authorFerrón, Pablo
dc.contributor.authorAizpurua Iparraguirre, Jesus Mari
dc.contributor.authorLlop, Jordi
dc.date.accessioned2025-06-09T08:12:45Z
dc.date.available2025-06-09T08:12:45Z
dc.date.issued2023-01-18
dc.date.updated2025-06-09T08:12:45Z
dc.description.abstractBackground and objective: The determination of pharmacokinetic properties of new chemical entities is a key step in the process of drug development. Positron emission tomography (PET) is an ideal technique to obtain both biodistribution and pharmacokinetic parameters of new compounds over a wide range of chemical modalities. Here, we use a multi-radionuclide/multi-position labelling approach to investigate distribution, elimination, and metabolism of a triazole-based FKBP12 ligand (AHK2) with potential application in neuromuscular disorders. Methods: Target engagement and stabilizing capacity of the drug candidate (AHK2) towards FKBP12-RyR was evaluated using competitive ligand binding and proximity ligation assays, respectively. Subsequently, AHK2 was labelled either with the positron emitter carbon-11 (11C) via 11C-methylation to yield both [11C]AHK2.1 and [11C]AHK2.2, or by palladium-catalysed reduction of the corresponding 5-iodotriazole derivative using 3H gas to yield [3H]AHK2. Metabolism was first investigated in vitro using liver microsomes. PET imaging studies in rats after intravenous (IV) administration at different doses (1 µg/Kg and 5 mg/Kg) were combined with determination of arterial blood time-activity curves (TACs) and analysis of plasma samples by high performance liquid chromatography (HPLC) to quantify radioactive metabolites. Arterial TACs were obtained in continuous mode by using an in-house developed system that enables extracorporeal blood circulation and continuous measurement of radioactivity in the blood. Pharmacokinetic parameters were determined by non-compartmental modelling of the TACs. Results: In vitro studies indicate that AHK2 binds to FKBP12 at the rapamycin-binding pocket, presenting activity as a FKBP12/RyR stabilizer. [11C]AHK2.1, [11C]AHK2.2 and [3H]AHK2 could be obtained in overall non-decay corrected radiochemical yields of 14 ± 2%, 15 ± 2% and 0.05%, respectively. Molar activities were 60–110 GBq/µmol, 68–122 GBq/µmol and 0.4–0.5 GBq/μmol, respectively. In vitro results showed that oxidation of the thioether group into sulfoxide, demethylation of the CH3O-Ar residue and demethylation of –N(CH3)2 were the main metabolic pathways. Fast metabolism was observed in vivo. Pharmacokinetic parameters obtained from metabolite-corrected arterial blood TACs showed a short half-life (12.6 ± 3.3 min). Dynamic PET imaging showed elimination via urine when [11C]AHK2.2 was administered, probably reflecting the biodistribution of [11C]methanol as the major metabolite. Contrarily, accumulation in the gastrointestinal track was observed after administration of [11C]AKH2.1. Conclusions: AHK2 binds to FKBP12 at the rapamycin-binding pocket, presenting activity as a FKBP12/RyR stabilizer. Studies performed with the 3H- and 11C-labelled FKBP12/RyR stabilizer AHK2 confirm fast blood clearance, linear pharmacokinetics and rapid metabolism involving oxidation of the sulfide and amine moieties and oxidative demethylation of the CH3-O-Ar and tertiary amine groups as the main pathways. PET studies suggest that knowledge about metabolic pathways is paramount to interpret images.en
dc.description.sponsorshipThe work was supported by MCIN/AEI/10.13039/501100011033 (PID2020-117656RB-I00 and PID2020-119780RB-I00), Interreg Atlantic Area Programme (EAPA_791/2018), and the European Commission (H2020-MSCA-ITN-2015-ETN; ID: 675417). This work was performed under the Maria de Maeztu Units of Excellence Programme—Grant MDM-2017-0720, funded by MCIN/AEI/10.13039/501100011033. Basque Government funding (GIC-2022_IT1741-22 and IT_01312)is also acknowledged. PMM holds a PhD Fellowship from Fundación Jesús de Gangoiti Barreraen
dc.identifier.citationPassannante, R., Gómez-Vallejo, V., Sagartzazu-Aizpurua, M., Vignau Arsuaga, L., Marco-Moreno, P., Aldanondo, G., Vallejo-Illarramendi, A., Aguiar, P., Cossío, U., Martín, A., Bergare, J., Kingston, L., Elmore, C. S., Morcillo, M. A., Ferrón, P., Aizpurua, J. M., & Llop, J. (2023). Pharmacokinetic evaluation of new drugs using a multi-labelling approach and PET imaging: application to a drug candidate with potential application in neuromuscular disorders. Biomedicines, 11(2). https://doi.org/10.3390/BIOMEDICINES11020253
dc.identifier.doi10.3390/BIOMEDICINES11020253
dc.identifier.eissn2227-9059
dc.identifier.urihttps://hdl.handle.net/20.500.14454/2972
dc.language.isoeng
dc.publisherMDPI
dc.rights© 2023 by the authors
dc.subject.otherPET
dc.subject.otherPharmacokinetics
dc.subject.otherRadiolabelling
dc.titlePharmacokinetic evaluation of new drugs using a multi-labelling approach and PET imaging: application to a drug candidate with potential application in neuromuscular disordersen
dc.typejournal article
dcterms.accessRightsopen access
oaire.citation.issue2
oaire.citation.titleBiomedicines
oaire.citation.volume11
oaire.licenseConditionhttps://creativecommons.org/licenses/by/4.0/
oaire.versionVoR
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