4,4,16‐Trifluoropalmitate: design, synthesis, tritiation, radiofluorination and pre‐clinical PET imaging studies on myocardial fatty acid oxidation
journal contributionposted on 2020-09-09, 08:09 authored by Matteo Zanda, Alessandro Colombano, Sergio Dall'Angelo, Lee Kingston, Gunnar Grönberg, Claudia Correia, Rossana Passannante, Zuriñe Baz, Miguel Angel Morcillo, Charles Elmore, Jordi Llop
Fatty acid oxidation (FAO) produces the majority of ATP used to sustain the cardiac contractile work, while glycolysis is a secondary source of ATP under normal physiological conditions. FAO impairment has been reported in the advanced stages of Heart Failure (HF) and is strongly linked to disease progression and severity. Thus, from a clinical perspective, FAO dysregulation provides prognostic value for HF progression, whose assessment could be used to improve patients’ monitoring and therapy effectiveness. Positron emission tomography (PET) imaging represents a powerful tool for the assessment and quantification of metabolic pathways, in vivo. Several FAO PET tracers have been reported in the literature but none of them is in routine clinical use yet. Metabolically trapped tracers are particularly interesting, because they undergo FAO generating a radioactive metabolite, which is subsequently trapped in the mitochondria, thus providing a quantitative means of measuring FAO in vivo. Herein we describe the design, synthesis, tritium labelling and radiofluorination of 4,4,16‐trifluoro‐palmitate 1 as a novel potential metabolically trapped FAO tracer. Preliminary PET‐CT studies on [18F]1 in rats showed rapid blood clearance, good metabolic stability, confirmed using [3H]1 in vitro, and resistance towards defluorination. However cardiac uptake in rats was modest (0.24 ± 0.04% ID/g) and kinetic analysis showed reversible uptake, indicating that [18F]1 is not irreversibly trapped.
European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement N° 675417 (PET3D project).
Spanish Ministry of Economy and Competitiveness (CTQ2017-87637-R).
Maria de Maeztu Units of Excellence Programme – Grant No. MDM-2017-0720.
Pages2317 - 2331
- AM (Accepted Manuscript)
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Publisher statementThis is the peer reviewed version of the following article: Zanda, M., Colombano, A., Dall'Angelo, S., Kingston, L., Grönberg, G., Correia, C., Passannante, R., Baz, Z., Morcillo, M.A., Elmore, C. and Llop, J. (2020), 4,4,16‐Trifluoropalmitate: design, synthesis, tritiation, radiofluorination and pre‐clinical PET imaging studies on myocardial fatty acid oxidation. ChemMedChem, 15 (23), pp.2317-2331, which has been published in final form at https://doi.org/10.1002/cmdc.202000610. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.