Synthesis and Evaluation of 18F- and 11C-Labeled Phenyl-Galactopyranosides as Potential Probes for in Vivo Visualization of LacZ Gene Expression using Positron Emission To

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• 作者：Sofie Celen ; Christophe Deroose ; Tjibbe de Groot ; Satish K. Chitneni ; Rik Gijsbers ; Zeger Debyser ; Luc Mortelmans ; Alfons Verbruggen ; Guy Bormans
• 刊名：Bioconjugate Chemistry
• 出版年：2008
• 出版时间：February 2008
• 年：2008
• 卷：19
• 期：2
• 页码：441 - 449
• 全文大小：221K
• 年卷期：v.19,no.2(February 2008)
• ISSN：1520-4812

文摘

3-Hydroxy-2-nitrophenyl 2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside, a derivative of the chromogenic β-galactosidase (β-gal) substrate o-nitrophenyl β-D-galactopyranoside (ONPG) was synthesized using a Koenigs−Knorr glycosylation reaction. It was alkylated with 2-[¹⁸F]fluoroethyl triflate or [¹¹C]methyl triflate, followed by deacetylation of the sugar hydroxyl groups to obtain radiolabeled 3-(2′-[¹⁸F]fluoroethoxy)-2-nitrophenyl β-D-galactopyranoside ([¹⁸F]-2c) and 3-[¹¹C]methoxy-2-nitrophenyl β-D-galactopyranoside ([¹¹C]-3c), which were evaluated as potential reporter probes for in vivo visualization of LacZ gene expression with positron emission tomography (PET). In vitro, [¹⁸F]-2c and [¹¹C]-3c were good substrates of β-gal and showed, respectively, a 7.5- and 2.5-fold higher uptake into β-gal expressing cells (LacZ cells) compared to control cells. However, reversed-phase HPLC analysis of the LacZ cell lysate and supernatant showed that labeled 3-(2′-[¹⁸F]fluoroethoxy)-2-nitrophenol, the hydrolysis product formed by β-gal-mediated cleavage of [¹⁸F]-2c, substantially leaked out of the cells, which would lead to loss of PET signal. In a µPET study of [¹⁸F]-2c in a mouse with a β-gal expressing tumor, high retention was observed in liver and kidneys, but only negligible accumulation was seen in the tumor. As a general conclusion, it can be stated that the synthesized PET tracers [¹⁸F]-2c and [¹¹C]-3c are not suitable for use as LacZ reporter probes. Further structural modifications to improve the diffusion over the tumor cell membrane and to increase retention in β-gal expressing cells may lead to more favorable in vivo imaging probes.