Design and Investigation of a [18F]-Labeled Benzamide Derivative as a High Affinity Dual Sigma Receptor Subtype Radioligand for Prostate Tumor Imaging.

ABSTRACT: High overexpression of sigma (?) receptors (?1 and ?2 subtypes) in a variety of human solid tumors has prompted the development of ? receptor-targeting radioligands, as imaging agents for tumor detection. A majority of these radioligands to date target the ?2 receptor, a potential marker of tumor proliferative status. The identification of approximately equal proportions of both ? receptor subtypes in prostate tumors suggests that a high affinity, dual ? receptor-targeting radioligand could potentially provide enhanced tumor targeting efficacy in prostate cancer. To accomplish this goal, we designed a series of ligands which bind to both ? receptor subtypes with high affinity. Ligand 3a in this series, displaying optimal dual ? receptor subtype affinity (?1, 6.3 nM; ?2, 10.2 nM) was radiolabeled with fluorine-18 (18F) to give [18F]3a and evaluated as a ? receptor-targeting radioligand in the mouse PC-3 prostate tumor model. Cellular assays with PC-3 cells demonstrated that a major proportion of [18F]3a was localized to cell surface ? receptors, while ?10% of [18F]3a was internalized within cells after incubation for 3.5 h. Serial PET imaging in mice bearing PC-3 tumors revealed that uptake of [18F]3a was 1.6 ± 0.8, 4.4 ± 0.3, and 3.6 ± 0.6% ID/g (% injection dose per gram) in ? receptor-positive prostate tumors at 15 min, 1.5 h, and 3.5 h postinjection, respectively (n = 3) resulting in clear tumor visualization. Blocking studies conducted with haloperidol (a nonselective inhibitor for both ? receptor subtypes) confirmed that the uptake of [18F]3a was ? receptor-mediated. Histology analysis confirmed similar expression of ?1 and ?2 in PC-3 tumors which was significantly greater than its expression in normal organs/tissues such as liver, kidney, and muscle. Metabolite studies revealed that >50% of radioactivity in PC-3 tumors at 30 min postinjection represented intact [18F]3a. Prominent ? receptor-specific uptake of [18F]3a in prostate tumors and its subsequent clear visualization with PET imaging indicate potential utility for the diagnosis of prostate carcinoma.

SUBMITTER: Yang D 

PROVIDER: S-EPMC5490379 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature