Synthesis and in vivo evaluation of 2 high-affinity 76Br-labeled sigma2-receptor ligands

The sigma(2)-receptor has been shown to be upregulated in proliferating tumors cells. The purpose of this study was to compare 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) and 2 new (76)Br-radiolabeled compounds that have a high affinity and selectivity for the sigma(2)-receptor. These are 5-bromo-N-(4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butyl)-2,3-dimethoxybenzamide (compound (1)) and 5-bromo-N-(2-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)ethyl)-2-methoxybenzamide (compound (2)).

Two sigma(2)-receptor-binding ligands were prepared, from the corresponding tributylstannyl precursors using standard electrophilic chemistry, (76)Br-compound (1) ((76)Br-1) and (76)Br-compound (2) ((76)Br-2). (18)F-FLT, (76)Br-1, and (76)Br-2 were compared using allograft tumors of the EMT-6 cell line (mouse mammary adenocarcinoma) in biodistribution studies at 5 min, 0.5, 1, and 2 h. Imaging of (76)Br-1 and (18)F-FLT was also performed at 2 and 1 h, respectively.

(76)Br-1 and (76)Br-2 were synthesized with yields between 50% and 70% with high specific activity. Both compounds showed uptake into the tumor with tumor-to-normal tissue ratios of (76)Br-1 being greater than both (76)Br-2 and (18)F-FLT. Except for the liver and kidney, all ratios were greater than 1 and uptake into the tumor was shown with microPET imaging for (76)Br-1.

We were able to synthesize two (76)Br-radiolabeled compounds with a high yield and specific activity that target the sigma(2) receptor with high affinity and selectivity. The studies presented show that both of the flexible benzamide compounds can identify EMT-6 breast tumors in vivo. (76)Br-1 also has higher tumor-to-normal tissue ratios when compared with (76)Br-2 and (18)F-FLT. The high affinity and low nonspecific binding of (76)Br-1 indicates that it can be a potential PET radiotracer for imaging solid tumors.