Preclinical in vivo and in vitro comparison of the translocator protein PET ligands [18F]PBR102 and [18F]PBR111
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To determine the metabolic profiles of the translocator protein ligands PBR102 and PBR111 in rat and human microsomes and compare their in vivo binding and metabolite uptake in the brain of non-human primates (Papio hamadryas) using PET-CT.
In vitro metabolic profiles of PBR102 and PBR111 in rat and human liver microsomes were assessed by liquid chromatography–tandem mass spectrometry. [18F]PBR102 and [18F]PBR111 were prepared by nucleophilic substitution of their corresponding p-toluenesulfonyl precursors with [18F]fluoride. List mode PET-CT brain imaging with arterial blood sampling was performed in non-human primates. Blood plasma measurements and metabolite analysis, using solid-phase extraction, provided the metabolite profile and metabolite-corrected input functions for kinetic model fitting. Blocking and displacement PET-CT scans, using PK11195, were performed.
Microsomal analyses identified the O-de-alkylated, hydroxylated and N-de-ethyl derivatives of PBR102 and PBR111 as the main metabolites. The O-de-alkylated compounds were the major metabolites in both species; human liver microsomes were less active than those from rat. Metabolic profiles in vivo in non-human primates and previously published rat experiments were consistent with the microsomal results. PET-CT studies showed that K1 was similar for baseline and blocking studies for both radiotracers; VT was reduced during the blocking study, suggesting low non-specific binding and lack of appreciable metabolite uptake in the brain.
[18F]PBR102 and [18F]PBR111 have distinct metabolic profiles in rat and non-human primates. Radiometabolites contributed to non-specific binding and confounded in vivo brain analysis of [18F]PBR102 in rodents; the impact in primates was less pronounced. Both [18F]PBR102 and [18F]PBR111 are suitable for PET imaging of TSPO in vivo. In vitro metabolite studies can be used to predict in vivo radioligand metabolism and can assist in the design and development of better radioligands.
KeywordsTSPO [18F]PBR102 [18F]PBR111 Microsomes Metabolism Non-human primate PET-CT
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.
- 14.Katsifis A, Loc’h C, Henderson D, Bourdier T, Pham T, Greguric I, et al. A rapid solid-phase extraction method for measurement of non-metabolised peripheral benzodiazepine receptor ligands, [18F]PBR102 and [18F]PBR111, in rat and primate plasma. Nucl Med Biol. 2011;38:137–48. doi: 10.1016/j.nucmedbio.2010.07.008.CrossRefGoogle Scholar
- 15.Wilson AA, McCormick P, Kapur S, Willeit M, Garcia A, Hussey D, et al. Radiosynthesis and evaluation of [11C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol as a potential radiotracer for in vivo imaging of the dopamine D2 high-affinity state with positron emission tomography. J Med Chem. 2005;48:4153–60. doi: 10.1021/jm050155n.CrossRefGoogle Scholar
- 16.Fookes CJ, Pham TQ, Mattner F, Greguric I, Loc’h C, Liu X, et al. Synthesis and biological evaluation of substituted [18F]imidazo[1,2-a]pyridines and [18F]pyrazolo[1,5-a]pyrimidines for the study of the peripheral benzodiazepine receptor using positron emission tomography. J Med Chem. 2008;51:3700–12.CrossRefGoogle Scholar
- 21.Shetty HU, Zoghbi SS, Simeon FG, Liow JS, Brown AK, Kannan P, et al. Radiodefluorination of 3-fluoro-5-(2-(2-[18F](fluoromethyl)-thiazol-4-yl)ethynyl)benzonitrile ([18F]SP203), a radioligand for imaging brain metabotropic glutamate subtype-5 receptors with positron emission tomography, occurs by glutathionylation in rat brain. J Pharmacol Exp Ther. 2008;327:727–35. doi: 10.1124/jpet.108.143347.CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Yokoi T, Iida H, Itoh H, Kanno I. A new graphic plot analysis for cerebral blood flow and partition coefficient with iodine-123-iodoamphetamine and dynamic SPECT validation studies using oxygen-15-water and PET. J Nucl Med. 1993;34:498–505.Google Scholar
- 24.Knust EJ, Kupfernagel C, Stocklin G. Long-chain F-18 fatty acids for the study of regional metabolism in heart and liver; odd-even effects of metabolism in mice. J Nucl Med. 1979;20:1170–5.Google Scholar
- 25.Zoghbi SS, Shetty HU, Ichise M, Fujita M, Imaizumi M, Liow JS, et al. PET imaging of the dopamine transporter with 18F-FECNT: a polar radiometabolite confounds brain radioligand measurements. J Nucl Med. 2006;47:520–7.Google Scholar
- 28.Mori T, Sun LQ, Kobayashi M, Kiyono Y, Okazawa H, Furukawa T, et al. Preparation and evaluation of ethyl [18F]fluoroacetate as a proradiotracer of [18F]fluoroacetate for the measurement of glial metabolism by PET. Nucl Med Biol. 2009;36:155–62. doi: 10.1016/j.nucmedbio.2008.11.006.CrossRefGoogle Scholar
- 29.Peyronneau MA, Saba W, Dolle F, Goutal S, Coulon C, Bottlaender M, et al. Difficulties in dopamine transporter radioligand PET analysis: the example of LBT-999 using [18F] and [11C] labelling: part II: metabolism studies. Nucl Med Biol. 2012;39:347–59. doi: 10.1016/j.nucmedbio.2011.09.006.CrossRefGoogle Scholar
- 36.Saba W, Goutal S, Kuhnast B, Dolle F, Auvity S, Fontyn Y, et al. Differential influence of propofol and isoflurane anesthesia in a non-human primate on the brain kinetics and binding of [18F]DPA-714, a positron emission tomography imaging marker of glial activation. Eur J Neurosci. 2015;42:1738–45. doi: 10.1111/ejn.12946.CrossRefGoogle Scholar