Stabilised 111In-labelled DTPA- and DOTA-conjugated neurotensin analogues for imaging and therapy of exocrine pancreatic cancer

Abstract

Neurotensin (NT) receptors are overexpressed in exocrine pancreatic cancer and Ewing's sarcoma. The potential utility of native NT in cancer diagnosis and therapy is, however, limited by its rapid degradation in vivo. Therefore, NT analogues were synthesised with modified lysine and arginine derivatives to enhance stability and coupled either to DTPA, to enable high specific activity labelling with indium-111 for imaging, or to DOTA, to enable high specific activity labelling with beta-emitting radionuclides, such as lutetium-177 and yttrium-90. Based on serum stability (4 h incubation at 37 degrees C in human serum) and receptor binding affinity, the five most promising analogues were selected and further evaluated in in vitro internalisation studies in human colorectal adenocarcinoma HT29 cells, which overexpress NT receptors. All five NT analogues bound with high affinity to NT receptors on human exocrine pancreatic tumour sections. The analogues could be labelled with (111)In to a high specific activity. The (111)In-labelled compounds were found to be very stable in serum. Incubation of HT29 cells with the (111)In-labelled analogues at 37 degrees C showed rapid receptor-mediated uptake and internalisation. The most promising analogue, peptide 2530 [DTPA-(Pip)Gly-Pro-(PipAm)Gly-Arg-Pro-Tyr-tBuGly-Leu-OH] was further tested in vivo in a biodistribution study using HT29 tumour-bearing nude mice. The results of this study showed low percentages of injected dose per gram tissue of this (111)In-labelled 2530 analogue in receptor-negative organs like blood, spleen, pancreas, liver, muscle and femur. Good uptake was found in the receptor-positive HT29 tumour and high uptake was present in the kidneys. Co-injection of excess unlabelled NT significantly reduced tumour uptake, showing that tumour uptake is a receptor-mediated process. With their enhanced stability, maintained high receptor affinity and rapid receptor-mediated internalisation, the (111)In-labelled DTPA- and DOTA-conjugated NT analogues are excellent candidates for imaging and therapy of exocrine pancreatic cancer, peptide 2530 being the most promising analogue.

Facile Preparation of a Thiol-Reactive 18F-Labeling Agent and Synthesis of 18F-DEG-VS-NT for PET Imaging of a Neurotensin Receptor–Positive Tumor

“…To improve the in vivo stability, various NT analogs have been developed. For example, several radiolabeled NT analogs were recently developed as a valuable tool for both imaging and therapy of NTR-positive tumors (30)(31)(32)(33)(34)(35). Although encouraging results have been obtained in these initial studies, the relatively high kidney uptake and suboptimal tumor-to-tissue contrast warrant further improvement of these agents, especially in the choice of the radiolabel.…”

Added value of gastrin receptor scintigraphy in comparison to somatostatin receptor scintigraphy in patients with carcinoids and other neuroendocrine tumours

“…Thus, their additional value in comparison to Octreotide with respect to targeting of new receptors is limited. The potential additional value of other non-sstr targeting peptides is abated by other properties, such as an unfavourable biodistribution with high background for example (Virgolini et al 1994, Blum et al 2000, Decristoforo et al 2000, Hessenius et al 2000, Grewal et al 2002, Janssen et al 2002, De Visser et al 2003, Gotthardt et al 2004.…”

Synthesis and biological activity of stable branched neurotensin peptides for tumor targeting

“…In particular, we found that the tetrabranched form of neurotensin and NT(8-13) is stable for 24 h in human plasma and serum and has receptor affinity, which in the case of tetrabranched NT (8)(9)(10)(11)(12)(13), is higher than that of the monomeric peptide (22,23).…”

“…A truncated COOH-terminal fragment NT (8)(9)(10)(11)(12)(13)) is slightly more stable while maintaining neurotensin receptor affinity. However, even the half-life of NT(8-13) is too brief for tumor targeting in vivo (10).…”