Pharmacokinetic Evaluation of New Drugs Using a Multi-Labelling Approach and PET Imaging: Application to a Drug Candidate with Potential Application in Neuromuscular Disorders
dc.contributor.author | Passannante, Rossana | |
dc.contributor.author | Gómez Vallejo, Vanessa | |
dc.contributor.author | Sagartzazu Aizpurua, Maialen | |
dc.contributor.author | Vignau Arsuaga, Laura | |
dc.contributor.author | Marco Moreno, Pablo | |
dc.contributor.author | Aldanondo Aristizabal, Garazi | |
dc.contributor.author | Vallejo Illarramendi, Ainara ![]() | |
dc.contributor.author | Aguiar, Pablo | |
dc.contributor.author | Cossío, Unai | |
dc.contributor.author | Martín, Abraham ![]() | |
dc.contributor.author | Bergare, Jonas | |
dc.contributor.author | Kingston, Lee | |
dc.contributor.author | Elmore, Charles S. | |
dc.contributor.author | Morcillo Alonso, Miguel Ángel | |
dc.contributor.author | Ferrón, Pablo | |
dc.contributor.author | Aizpurua Iparraguirre, Jesús María ![]() | |
dc.contributor.author | Llop Roig, Jordi ![]() | |
dc.date.accessioned | 2023-02-28T14:49:26Z | |
dc.date.available | 2023-02-28T14:49:26Z | |
dc.date.issued | 2023-01-18 | |
dc.identifier.citation | Biomedicines 11(2) : (2023) // Article ID 253 | es_ES |
dc.identifier.issn | 2227-9059 | |
dc.identifier.uri | http://hdl.handle.net/10810/60143 | |
dc.description.abstract | Background 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. | es_ES |
dc.description.sponsorship | The 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 Barrera. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | MDPI | es_ES |
dc.relation | info:eu-repo/grantAgreement/EC/H2020/675417 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICIU/MDM-2017-0720 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/PID2020-117656RB-I00 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/PID2020-119780RB-I00 | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | PET | es_ES |
dc.subject | radiolabelling | es_ES |
dc.subject | pharmacokinetics | es_ES |
dc.title | Pharmacokinetic Evaluation of New Drugs Using a Multi-Labelling Approach and PET Imaging: Application to a Drug Candidate with Potential Application in Neuromuscular Disorders | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.date.updated | 2023-02-24T14:08:09Z | |
dc.rights.holder | © 2022 by the authors.Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/ 4.0/). | es_ES |
dc.relation.publisherversion | https://www.mdpi.com/2227-9059/11/2/253 | es_ES |
dc.identifier.doi | 10.3390/biomedicines11020253 | |
dc.contributor.funder | European Commission | |
dc.departamentoes | Química orgánica I | |
dc.departamentoeu | Kimika organikoa I |
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Except where otherwise noted, this item's license is described as © 2022 by the authors.Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/ 4.0/).