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On fluoro-18 labeling of bile acids
Nuclear Medicine and Biology 41 (2014) 775
Contents lists available at ScienceDirect
Nuclear Medicine and Biology journal homepage: www.elsevier.com/locate/nucmedbio
Letter to the Editor
On fluoro-18 labeling of bile acids Dear Sir, The development of bile acid derived ligands for the nuclear receptor farnesoid X receptor (FXR) is an intensively studied area of research with immense therapeutic potential in hepatic and intestinal diseases. Of equal importance and with great prospect in drug development and clinical evaluation of cholestatic patients is the development of radioactively labeled bile acid analogues for positron emission tomography (PET). In the issue of July 2014, Jia et al. reported on a novel 18F-labeled bile acid compound as a potential PET tracer for FXR-related diseases [1], which we read with great interest. As parent bile acid, Jia et al. reasonably chose chenodeoxycholic acid (CDCA), the most potent endogenous ligand for FXR. However, they derivatized CDCA at C-24 with a terminal alkyne for subsequent radiolabeling with a 18F-labeled azide via the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction. The resulting tracer, an N-acyl amidate of CDCA and 1-[1-(2-[ 18F]fluoroethyl)-1H-1,2,3-triazole-4-yl]methanamine, referred to in reference [1] as [ 18F]8, thus has the characteristic steroidal backbone of CDCA, but lacks the acid group on the side-chain, which is a common and characteristic feature of all endogenous bile acids. Since an acid group on the side-chain is not prerequisite for a bile acid derivative to be a ligand for FXR [2], [ 18F]8 may indeed be considered a potential PET ligand for FXR, although its affinity remains to be investigated. Moreover, based on its lipophilicity, hepatic uptake and biliary excretion, Jia et al. also conclude that [ 18F]8 have properties similar to those of the parent bile acid, CDCA, and consider it as 18F-labeled CDCA. Their observations, however, do not ensure that [18F]8 behaves like CDCA or, in particular, follows the same transport mechanism as CDCA. Many large and lipophilic compounds, derived from bile acids or not, anionic, cationic or neutral, are taken up by the liver and excreted into bile by a number of different transport mechanisms [3,4]. An acid group on a bile acid derivative, providing a negative charge on the C-24 at sufficiently high pH, is not prerequisite for hepatic or intestinal transport, but it does have an important influence on the mechanism of transport [5,6]. The lipophilicity of a bile acid derivative with an acid group strongly depends on whether it is
http://dx.doi.org/10.1016/j.nucmedbio.2014.07.001 0969-8051/© 2014 Elsevier Inc. All rights reserved.
protonated or deprotonated; protonated species being more lipophilic and prone to passive absorption, while deprotonated species are less lipophilic requiring active transport to enter cells. In the case of the presented tracer, [ 18F]8, its reported lipophilicity (logD) is between that of non-amidate and amidate CDCA [1,7] which are transported by quite different mechanisms [8]. Thus, [ 18F]8 is not a 18F-labeled bile acid—and certainly not 18F-labeled CDCA.
Kim Frisch⁎ Michael Sørensen Department of Nuclear Medicine and PET Center Aarhus University Hospital, Aarhus, Denmark ⁎Corresponding author. E-mail address: [email protected]
References [1] Jia L, Jiang D, Hu P, Li X, Shi H, Cheng D, et al. Synthesis and evaluation of 18F-labeled bile acid compound: a potential PET imaging agent for FXR-related diseases. Nucl Med Biol 2014;41:495–500. [2] Merk D, Steinhilber D, Schubert-Zsilavecz M. Medicinal chemistry of farnesoid X receptor ligands: from agonists and antagonist to modulators. Future Med Chem 2012;4:1015–36. [3] Hagenbuch B. Drug uptake systems in liver and kidney: historic perspective. Clin Pharmacol Ther 2010;87:39–47. [4] Bohan A, Boyer JL. Mechanisms of hepatic transport of drugs: implications for cholestatic drug reactions. Semin Liver Dis 2002;22:123–36. [5] Sievänen E. Exploitation of bile acid transport systems in prodrug design. Molecules 2007;12:1859–89. [6] Hardison WGM, Heasley VL, Shellhamer DF. Specificity of the hepatocyte Na+-dependent taurocholate transporter: influence of side chain length and charge. Hepatology 1991;13:68–72. [7] Roda A, Minutello A, Angellotti MA, Fini A. Bile acid structure-activity relationship: evaluation of bile acid lipophilicity using 1-octanol/water partition coefficient and reverse phase HPLC. J Lipid Res 1990;31:1433–43. [8] Hofmann AF, Hagey LR. Bile acids: chemistry, pathochemistry, biology, patholiology, and therapeutics. Cell Mol Life Sci 2008;65:2461–83.
Contents lists available at ScienceDirect
Nuclear Medicine and Biology journal homepage: www.elsevier.com/locate/nucmedbio
Letter to the Editor
On fluoro-18 labeling of bile acids Dear Sir, The development of bile acid derived ligands for the nuclear receptor farnesoid X receptor (FXR) is an intensively studied area of research with immense therapeutic potential in hepatic and intestinal diseases. Of equal importance and with great prospect in drug development and clinical evaluation of cholestatic patients is the development of radioactively labeled bile acid analogues for positron emission tomography (PET). In the issue of July 2014, Jia et al. reported on a novel 18F-labeled bile acid compound as a potential PET tracer for FXR-related diseases [1], which we read with great interest. As parent bile acid, Jia et al. reasonably chose chenodeoxycholic acid (CDCA), the most potent endogenous ligand for FXR. However, they derivatized CDCA at C-24 with a terminal alkyne for subsequent radiolabeling with a 18F-labeled azide via the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction. The resulting tracer, an N-acyl amidate of CDCA and 1-[1-(2-[ 18F]fluoroethyl)-1H-1,2,3-triazole-4-yl]methanamine, referred to in reference [1] as [ 18F]8, thus has the characteristic steroidal backbone of CDCA, but lacks the acid group on the side-chain, which is a common and characteristic feature of all endogenous bile acids. Since an acid group on the side-chain is not prerequisite for a bile acid derivative to be a ligand for FXR [2], [ 18F]8 may indeed be considered a potential PET ligand for FXR, although its affinity remains to be investigated. Moreover, based on its lipophilicity, hepatic uptake and biliary excretion, Jia et al. also conclude that [ 18F]8 have properties similar to those of the parent bile acid, CDCA, and consider it as 18F-labeled CDCA. Their observations, however, do not ensure that [18F]8 behaves like CDCA or, in particular, follows the same transport mechanism as CDCA. Many large and lipophilic compounds, derived from bile acids or not, anionic, cationic or neutral, are taken up by the liver and excreted into bile by a number of different transport mechanisms [3,4]. An acid group on a bile acid derivative, providing a negative charge on the C-24 at sufficiently high pH, is not prerequisite for hepatic or intestinal transport, but it does have an important influence on the mechanism of transport [5,6]. The lipophilicity of a bile acid derivative with an acid group strongly depends on whether it is
http://dx.doi.org/10.1016/j.nucmedbio.2014.07.001 0969-8051/© 2014 Elsevier Inc. All rights reserved.
protonated or deprotonated; protonated species being more lipophilic and prone to passive absorption, while deprotonated species are less lipophilic requiring active transport to enter cells. In the case of the presented tracer, [ 18F]8, its reported lipophilicity (logD) is between that of non-amidate and amidate CDCA [1,7] which are transported by quite different mechanisms [8]. Thus, [ 18F]8 is not a 18F-labeled bile acid—and certainly not 18F-labeled CDCA.
Kim Frisch⁎ Michael Sørensen Department of Nuclear Medicine and PET Center Aarhus University Hospital, Aarhus, Denmark ⁎Corresponding author. E-mail address: [email protected]
References [1] Jia L, Jiang D, Hu P, Li X, Shi H, Cheng D, et al. Synthesis and evaluation of 18F-labeled bile acid compound: a potential PET imaging agent for FXR-related diseases. Nucl Med Biol 2014;41:495–500. [2] Merk D, Steinhilber D, Schubert-Zsilavecz M. Medicinal chemistry of farnesoid X receptor ligands: from agonists and antagonist to modulators. Future Med Chem 2012;4:1015–36. [3] Hagenbuch B. Drug uptake systems in liver and kidney: historic perspective. Clin Pharmacol Ther 2010;87:39–47. [4] Bohan A, Boyer JL. Mechanisms of hepatic transport of drugs: implications for cholestatic drug reactions. Semin Liver Dis 2002;22:123–36. [5] Sievänen E. Exploitation of bile acid transport systems in prodrug design. Molecules 2007;12:1859–89. [6] Hardison WGM, Heasley VL, Shellhamer DF. Specificity of the hepatocyte Na+-dependent taurocholate transporter: influence of side chain length and charge. Hepatology 1991;13:68–72. [7] Roda A, Minutello A, Angellotti MA, Fini A. Bile acid structure-activity relationship: evaluation of bile acid lipophilicity using 1-octanol/water partition coefficient and reverse phase HPLC. J Lipid Res 1990;31:1433–43. [8] Hofmann AF, Hagey LR. Bile acids: chemistry, pathochemistry, biology, patholiology, and therapeutics. Cell Mol Life Sci 2008;65:2461–83.