Synthesis and in vivo evaluation of 2 high-affinity ⁷⁶Br-labeled σ₂-receptor ligands

The σ₂-receptor has been shown to be upregulated in proliferating tumors cells. The purpose of this study was to compare 3′-deoxy-3′-¹⁸F-fluorothymidine (¹⁸F-FLT) and 2 new ⁷⁶Br-radiolabeled compounds that have a high affinity and selectivity for the σ₂-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)). Methods: Two σ₂- receptor-binding ligands were prepared, from the corresponding tributylstannyl precursors using standard electrophilic chemistry, ⁷⁶Br-compound (1) (⁷⁶Br-1) and ⁷⁶Br-compound (2) (⁷⁶Br-2). ¹⁸F-FLT, ⁷⁶Br-1, and ⁷⁶Br-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 ⁷⁶Br-1 and ¹⁸F-FLT was also performed at 2 and 1 h, respectively. Results: ⁷⁶Br-1 and ⁷⁶Br-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 ⁷⁶Br-1 being greater than both ⁷⁶Br-2 and ¹⁸F-FLT. Except for the liver and kidney, all ratios were greater than 1 and uptake into the tumor was shown with microPET imaging for ⁷⁶Br-1. Conclusion: We were able to synthesize two 76Br-radiolabeled compounds with a high yield and specific activity that target the σ₂ 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. ⁷⁶Br-1 also has higher tumor-to-normal tissue ratios when compared with ⁷⁶Br-2 and ¹⁸F-FLT. The high affinity and low nonspecific binding of ⁷⁶Br-1 indicates that it can be a potential PET radiotracer for imaging solid tumors.