Overexpression of
sigma-2 receptors in human
tumors, such as
melanoma,
breast cancer,
small cell lung carcinoma and
prostate cancer, has been reported. Furthermore, the expression of
sigma-2 receptors parallels the proliferative status of
breast tumors implanted in nude mice. Thus, radiolabeled probes with a high affinity and high selectivity targeting
sigma-2 receptors may be useful as
tumor imaging agents. A conformationally flexible
benzamide derivative, 5-bromo-2,3-dimethoxy-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl]-
benzamide, displayed greater than 1,000-fold selectivity for
sigma-2 receptors (K(i)=8.2 and 12,900 nM for sigma-2 and sigma-1, respectively). The corresponding radioiodinated
ligand, 5-iodo-2,3-dimethoxy-N-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl]-
benzamide ([(125)I]/[(123)I]I), was successfully prepared via an iododestannylation reaction. Binding studies carried out in membrane homogenates prepared from the mouse mammary tumor cell line (EMT6) with [(125)I]I showed the desired high binding affinity and high capacity (K(d)=0.68+/-0.06 nM, B(max)=1,005+/-46 fmol/mg
protein). The sigma-2-like pharmacological profile of [(125)I]I binding sites was confirmed by competition studies. Similar binding parameters were also found in EMT6 xenografts (Day 10 and Day 19 implants) from BALB/c mice (K(d)=0.43-1.1 nM, B(max)=2,025-4,528 fmol/mg
protein). It was determined by dissection and microSPECT imaging that [(125)I]/[(123)]I accumulated in EMT6
tumors established in BALB/c mice (Day 10 implants). Two hours after the tracer injection, the dissection ratio of EMT6
tumor to background (muscle) reached 6-7. However, microSPECT imaging could not clearly delineate the
tumors, while the specific localization could be confirmed by ex vivo autoradiography. In summary, the novel iodinated
ligand with high affinity and considerable selectivity for
sigma-2 receptors may provide a useful tool to characterize
sigma-2 receptors in vitro. Further modification of the
ligand and the imaging parameters will be needed to improve the signal for in vivo detection.