Radiolabeled somatostatin receptor antagonists are preferable to agonists forin vivopeptide receptor targeting of tumors

Abstract

antagonist radioligands ͉ tumor targeting ͉ peptide hormones ͉ neuropeptides ͉ receptor internalization P eptide receptor targeting in vivo is a successful method to image and treat various types of cancers (1). The best example is somatostatin receptor targeting with 111 In-, 90 Y-, or 177 Lu-labeled somatostatin radioligands that are injected into the patients intravenously and accumulate in their somatostatin receptor-expressing tumors. For this purpose, agonists have been selected. The rationale is that agonists, after high-affinity binding to the receptor, usually trigger internalization of the ligandreceptor complex (2). This process of internalization is the basis for an efficient accumulation of the radioligand in a cell over time (1,(3)(4)(5), and it has been considered a crucial step in the process of in vivo receptor targeting with radiolabeled peptides (4-6). Recently, a highly significant correlation between the rate of ligand internalization in vitro into AR42J cells expressing somatostatin receptor subtype 2 (sst 2 ) and the in vivo uptake in the sst 2 -expressing rat tumor model has been reported

Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma

“…The biodistribution profiles of acetazolamide derivatives compares favourably with the ones previously reported for other ligands [23][24][25][26]. In particular, we were pleased to see that %ID/g values in the tumor were higher than the corresponding values in the kidney (the main organ for drug clearance), even as early as one hour after intravenous administration of the product [18].…”

“…Unlike antibodies (which can easily be raised against the majority of target proteins of interest), it is not always easy to generate high-affinity small molecule ligands to tumor-associated antigens. However, excellent tumor-targeting results have been reported for folate analogues targeting folate-receptor positive tumors [23,24], substituted urea derivatives targeting prostate-specific membrane antigen [25], somatostatin antagonists targeting the somatostatin receptor [26] and for carbonic anhydrase IX (CAIX) ligands [16][17][18]27].…”

Radiopharmaceuticals for somatostatin receptor imaging

“…The same tendency was seen for both sst2 and sst3 selective analogs, suggesting that this observation may be valid for more than just one particular G-protein-coupled receptor. The study demonstrated that the sst antagonists are preferable for in vivo tumor targeting [73]. The first clinical evaluation of SRS with an antagonist confirmed the pre-clinical data, as it showed higher tumor uptake of the antagonist In-DTPA 0 -octreotide and improved tumor-to-background ratios, in particular tumor-to-kidney [74].…”

“…Recent developments have indicated that receptor antagonists may be as good as or even better than agonists for such purposes. Ginj et al (2006) showed that high-affinity somatostatin receptor antagonists that poorly internalize into tumor cells can, in terms of in vivo uptake in animal tumors, perform equally good or better than corresponding agonists, which highly internalized into tumor cells. They provided potentially even better tumor visualization than agonists.…”

Synthesis and Characterization of a High-Affinity NOTA-Conjugated Bombesin Antagonist for GRPR-Targeted Tumor Imaging

“…These data was in a good agreement with the findings of other researchers. 14,23 The biodistribution of 111 In-and 68 Ga-labeled peptides in normal mice demonstrated specific uptake of the compounds in receptor-positive organs in the abdominal area (e.g. pancreas, stomach, small intestine and spleen).…”