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Synthesis and In Vivo Evaluation of 2 High-Affinity 76Br-Labeled {sigma}2-Receptor Ligands

Douglas J. Rowland, Zhude Tu, Jinbin Xu, Datta Ponde, Robert H. Mach and Michael J. Welch

Department of Radiology, Washington University in St. Louis, Saint Louis, Missouri


Figure 1
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  		FIGURE 1.  Compounds used in this work. Compounds (1) and (2) are benzamide analogs that target {sigma}2-receptor with high affinity and high selectivity over {sigma}1-receptor. Both were radiolabeled with 76Br for biodistribution and imaging studies. Compound (1) is 5-bromo-N-(4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butyl)-2,3-dimethoxybenzamide and compound (2) is 5-bromo-N-(2-(3,4-dihydro-6,7-dimethoxyi-soquinolin-2(1H)-yl)ethyl)-2-methoxybenzamide. Compound (3) is a fluorinated analog that was prepared for possible labeling with 18F. Compound (4) was used for Scatchard analysis to determine the nonspecific binding of 76Br-1. Compound (5) was used as a nonselective {sigma}1/{sigma}2 compound for blocking {sigma}2-receptor in animal receptor–blocking studies.

 

Figure 2
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  		FIGURE 2.  Generalized synthesis of 76Br-radiolabeled {sigma}2-ligands (1) and (2).

 

Figure 3
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  		FIGURE 3.  Bar chart shows comparison of ratio data between 76Br-1, 76Br-2, and 18F-FLT at 2 h. Brain is not shown because of high ratio for 76Br-1 (see text). ANOVA showed significance of tumor ratios at level of P ≤ 0.001. Cross-comparison between compounds using a Student t test showed no significance between 76Br-1 and 18F-FLT for liver, kidney, and fat and no significance between 76Br-1 and 76Br-2 for bone; all other values were significant at P ≤ 0.05. Data are presented as mean ± SD.

 

Figure 4
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  		FIGURE 4.  microPET image of 3 BALB/c mice implanted with EMT-6 cells and imaged with 18F-FLT (A), 76Br-1 nonblocked (B), and 76Br-1 with a blocking dose of compound (5) (C). Animals were imaged in supine position. Arrows in the images point to the tumor and in the case of FLT a second arrow points to the brain.

 

Figure 5
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  		FIGURE 5.  Scatchard analysis of 76Br-1 binding to {sigma}2-receptors in membrane homogenates from EMT-6 mouse breast tumor allografts. (A) Representative saturation binding experiments that show total binding, nonspecific binding, and specific binding. (B) Scatchard plots that were used to determine Kd, Bmax, and nH values. Results are presented as mean ± SE of triplicate experiments.

 




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