Evaluation of Radioiodinated 1-[2-(3,4-Dimethoxyphenyl)ethyl]-4-(2-iodophenylpropyl)piperazine as a Tumor Diagnostic Agent with Functional Sigma Receptor Imaging by Single Photon Emission Computed Tomography

Abstract

Sigma receptors were suggested as subtypes of the opiate receptors in 1976 by Martin et al.,1) however, later studies of the pharmacological binding and behavioral studies had to be modified that they were non-opiate and non-phencyclidine (PCP) binding site.2) From binding studies, sigma receptors have been classified into at least two subtypes, termed sigma-1 and sigma-2, for their pharmacological profiles and different molecular weights.2,3) Sigma-1 receptor is a Mr 25000 which protein was purified and cloned from the liver of guinea pig, 4) while sigma-2 receptor is a Mr 18000-21000 protein that has not yet been cloned. 2,3) Sigma receptors are present not only in the central nervous system but also in other tissues, such as the liver, kidneys, lungs, gonads, and ovaries.5-9) Moreover, sigma receptors are expressed in a variety of human tumors in high densities (1.0-1.5 million receptors/cell), such as malignant melanoma, 10) non-small-cell lung carcinoma, 11) breast cancer, 12) and tumors of neural origin.13) Interestingly, sigma receptors are highly expressed in rapidly proliferating cells and are down-regulated when cells become quiescent.14-16) Their high density in various tumor cell types, particularly in proliferating cells, makes sigma receptors potential targets for diagnostic imaging.Several radiolabeled ligands have been developed for the imaging of sigma receptors by single photon emission computed tomography (SPECT) [19][20][21][22][23] and positron emission tomography (PET). [24][25][26] We have explored the feasibility of using radioiodinated sigma receptor ligands for functional sigma receptor studies with SPECT, and have already reported the design, synthesis, and biological evaluation of iodinated SA4503 analogues.

Evaluation of radioiodinated vesamicol analogs for sigma receptor imaging in tumor and radionuclide receptor therapy

“…( 7,20 ) Therefore, nuclear imaging agents for sigma receptors could be useful in the differential diagnosis of tumors. ( 9 ) In this study, we first examined the potential of radioiodine‐labeled (+)‐ p IV, which has a very high affinity for sigma receptors, as a tumor‐imaging agent.…”

“…Furthermore, sigma receptors should be potential biomarkers of tumor proliferation because they are highly expressed in rapidly proliferating cells and are down‐regulated when cells become quiescent. ( 7–9 ) For the time being, radiolabeled sigma ligands should be useful for monitoring the effects of chemotherapy at an early stage when morphologic changes are not observed. ( 10 )…”

Sigma Receptors in Oncology: Therapeutic and Diagnostic Applications of Sigma Ligands

“…This suggests that it may be possible to non-invasively assess sigma receptor density, using SPECT and a radioiodinated sigma ligand. However, the authors did not present any microSPECT images [105].…”

“…Tumor-to-muscle ratios about 15 (B16) and 7 (A375) in nude mice, 24h after injection [105] 99m Tc-nitrido heterocomplex of 4-amino-…”

Development and evaluation of a novel radioiodinated vesamicol analog as a sigma receptor imaging agent

“…The high expression of sigma receptors in tumors suggests that they are appropriate targets for developing tumor-imaging agents. Furthermore, sigma receptors should be potential biomarkers of tumor proliferation because they are highly expressed in rapidly proliferating cells and are downregulated when cells become quiescent [15-17]. Meanwhile, sigma receptor ligands also could be candidate drugs for cancer therapy because some ligands have been reported to affect cell growth and apoptosis [18,19].…”