Background

[PubMed]

The ^99mTc-diethylenetriamine pentaacetic acid (DTPA)–lactosyl human serum albumin (HSA), abbreviated as ^99mTc-LACTAL, is a radiolabeled lactosylated ligand developed by Chaumet-Riffaud et al. for noninvasive assessment of liver function by targeting asialoglycoprotein receptors (ASGP-Rs) on the surface of hepatocytes (1).

Precise assessment of liver functional reserve has long been a critical issue in the diagnosis and treatment of liver diseases (2, 3). Various biochemical tests and imaging studies, such as laboratory tests, clearance and tolerance tests, functional imaging, and volumetric tests, have been designed to assess liver function (2, 4). Because of the complexity of liver function, there is no single method that is capable of assessing the overall liver function. Recently, an imaging technique involving ASGP-Rs and radiolabeled galactosylated ligands has been intensively investigated and shows great promise. ASGP-Rs are localized on the surface of hepatocytes and play a major role in the hepatic clearance of serum ASGPs with a galactosyl moiety. After binding with ASGP-Rs, ASGPs are endocytosed, degraded in the lysosomes, and excreted into the bile. In the settings of various liver diseases, both the number of ASGP-Rs and their function are significantly reduced (1-3). The blood clearance and binding with ASGP-Rs for a galactosylated ligand are thus considered to directly reflect the numbers of both functional ASGP-Rs and hepatocytes and can be used as indicators of liver functional reserve. In the literature, several galactosylated ligands have been reported, including Cy5.5-DTPA-galactosyl-dextran, ^99mTc-galactosyl-neoglycoalbumin (^99mTc-NGA), ^99mTc-DTPA-galactosyl-HSA (^99mTc-GSA), ^99mTc-galactosyl-methylated chitosan (^99mTc-GMC), ^99mTc-HYNIC-galactosyl-chitosan (^99mTc-HGC), ^99mTc-DTPA-superparamagnetic iron oxide-lactobionic acid nanoparticles (^99mTc-DTPA-SPION-LBA), and ¹⁸F-neoglycoalbumin ([¹⁸F]FNGA) (5-11). Of them, ^99mTc-GSA has been approved for clinical use in Japan. Imaging with ASGP-R–targeted ligands has provided a more precise assessment of the liver functional reserve than other measurements (e.g., biochemical tests, indocyanine green retention, and the Child-Pugh scoring system) (12). However, the synthetic procedures of these ligands, as noted by Chaumet-Riffaud et al., have a number of limitations: long reaction times, reduction of structural disulfide bonds, alterations of the net charge of the protein, or reactions involving toxic reagents such as sodium cyanoborohydride for reductive amination (1). Chaumet-Riffaud et al. developed an alternative process to prepare ^99mTc-LACTAL with maleimido-derivatized reagents. Preclinical studies validated the use of ^99mTc-LACTAL as a radiopharmaceutical agent for liver function imaging (1).

Synthesis

[PubMed]

Chaumet-Riffaud et al. described the synthesis of ^99mTc-LACTAL in detail (1). The process included maleimidopropyl-lactose (yield = 60%) and maleimidopropyl-DTPA (yield = 51%) synthesis, HSA modification, and ^99mTc chelating. Preparation of the LACTAL was finished in a quick single-step reaction involving maleimido-derivatized reagents (for 1 h at room temperature). The lactose and DTPA derivatives were introduced on the ε-amino groups of the HSA lysines. The amount of DTPA was 5 ± 1 DTPA/HSA (mol/mol), and the lactose concentration was 30 ± 3 lactose/HSA (mol/mol). The estimated mass of LACTAL was 93 kDa, which corresponded to 29 lactose units and 5 DTPA units.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Chaumet-Riffaud et al. checked the stability of the LACTAL solution after storage for 1 year at 4ºC and for 32 months at the lyophilized status (1). There were no differences from freshly prepared material, no aggregates were observed, and the imaging properties were identical. The ^99mTc-LACTAL solution was stable at room temperature for 20 h.

Animal Studies

Human Studies

[PubMed]

No references are currently available.

References

1.

Chaumet-Riffaud P., Martinez-Duncker I., Marty A.L., Richard C., Prigent A., Moati F., Sarda-Mantel L., Scherman D., Bessodes M., Mignet N. Synthesis and application of lactosylated, 99mTc chelating albumin for measurement of liver function. Bioconjug Chem. 2010;21(4):589–96. [PubMed: 20201600]

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Schneider P.D. Preoperative assessment of liver function. Surg Clin North Am. 2004;84(2):355–73. [PubMed: 15062650]

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Hoefs J.C., Chen P.T., Lizotte P. Noninvasive evaluation of liver disease severity. Clin Liver Dis. 2006;10(3):535–62. [PubMed: 17162227]

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de Graaf W., Bennink R.J., Vetelainen R., van Gulik T.M. Nuclear imaging techniques for the assessment of hepatic function in liver surgery and transplantation. J Nucl Med. 2010;51(5):742–52. [PubMed: 20395336]

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Kim E.M., Jeong H.J., Kim S.L., Sohn M.H., Nah J.W., Bom H.S., Park I.K., Cho C.S. Asialoglycoprotein-receptor-targeted hepatocyte imaging using 99mTc galactosylated chitosan. Nucl Med Biol. 2006;33(4):529–34. [PubMed: 16720245]

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Sugahara K., Togashi H., Takahashi K., Onodera Y., Sanjo M., Misawa K., Suzuki A., Adachi T., Ito J., Okumoto K., Hattori E., Takeda T., Watanabe H., Saito K., Saito T., Sugai Y., Kawata S. Separate analysis of asialoglycoprotein receptors in the right and left hepatic lobes using Tc-GSA SPECT. Hepatology. 2003;38(6):1401–9. [PubMed: 14647051]

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Yang W., Mou T., Peng C., Wu Z., Zhang X., Li F., Ma Y. Fluorine-18 labeled galactosyl-neoglycoalbumin for imaging the hepatic asialoglycoprotein receptor. Bioorg Med Chem. 2009;17(21):7510–6. [PubMed: 19796957]

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Yang W., Mou T., Zhang X., Wang X. Synthesis and biological evaluation of (99m)Tc-DMP-NGA as a novel hepatic asialoglycoprotein receptor imaging agent. Appl Radiat Isot. 2010;68(1):105–9. [PubMed: 19815422]

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Vera D.R., Hall D.J., Hoh C.K., Gallant P., McIntosh L.M., Mattrey R.F. Cy5.5-DTPA-galactosyl-dextran: a fluorescent probe for in vivo measurement of receptor biochemistry. Nucl Med Biol. 2005;32(7):687–93. [PubMed: 16243643]

12.

Kokudo N., Vera D.R., Makuuchi M. Clinical application of TcGSA. Nucl Med Biol. 2003;30(8):845–9. [PubMed: 14698788]