Comparative evaluation of 4 and 6-carbon spacer conformationally flexible tetrahydroisoquinolinyl benzamide analogues for imaging the sigma-2 receptor status of solid tumors.

Nine novel analogues were synthesized including a 6-carbon spacer analogue of ISO-1 (7). They have moderate binding affinity for sigma-2 (σ2) receptors and high selectivity for σ2 receptors relative to sigma-1 (σ1) receptors.([(18)F]7) was synthesized and evaluated as a candidate ligand for positron emission (PET) imaging of the σ2 receptor in tumors. Radioligand [(18)F]7 was radiolabeled with (18)F via displacement of the corresponding mesylate precursor with [(18)F]fluoride. Cellular uptake study of [(18)F]7 was performed in EMT-6 tumor cell, and in vivo biodistribution study of [(18)F]7 and microPET imaging study of [(18)F]3 and [(18)F]7 carried out in female Balb/c mice bearing EMT-6 tumors.[(18)F]7 had a respectable tumor uptake (1.55%ID/g at 60min post-injection) and high tumor/muscle ratios at 60 and 120min post-injection. MicroPET imaging of [(18)F]7 in tumor-bearing mice as above showed significant tumor localization and a high tumor/muscle ratio as well.These results are similar to or better than [(18)F]ISO-1 ([(18)F]3), which indicates that [(18)F]7 has potential for imaging the σ2 receptor status of solid tumors.