A stable neurotensin-based radiopharmaceutical for targeted imaging and therapy of neurotensin receptor-positive tumours

Abstract

Purpose Neurotensin (NT) and its high affinity receptor (NTR1) are involved in several neoplastic processes. Thus, NT-based radiopharmaceuticals are potential tracers for targeted diagnosis and therapy of NTR-positive tumours. A new analogue based on NT(8-13), NT-XIX, with the three enzymatic cleavage sites stabilised, was synthesised and tested. Methods The synthesis was performed by Boc strategy. Labelling with 99m Tc/ 188Re was performed using the tricarbonyl technique. Metabolic stability was tested in vitro and in vivo. NT-XIX was further characterised in vitro in HT-29 cells and in vivo in nude mice with HT-29 xenografts. Results NT-XIX showed much longer half-lives than nonstabilised analogues. Binding to NTR1 was highly specific, although the affinity was lower than that of natural NT. Bound activity rapidly internalised into HT-29 cells and 50% remained trapped after 24 h. In the time-course biodistribution, the highest uptake was found in the tumour at all p.i. times. In vivo uptake was specific, and accumulation of activity in the kidneys was low. Radioactivity clearance from healthy organs was faster than that from the tumour, resulting in improved tumour-to-tissue ratios and good SPECT/CT imaging. Treatment with 188 Re-NT-XIX (30 MBq, in three or four fractions) decreased tumour growth by 50% after 3 weeks. Conclusion The high in vivo stability and the favourable in vivo behaviour makes NT-XIX an excellent candidate for the imaging and therapy of NTR1-positive tumours.

Effect of a spacer moiety on radiometal labelled Neurotensin derivatives

“…Among other peptides investigated, Neurotensin (NT), or its binding sequence NT (8)(9)(10)(11)(12)(13) respectively, has been the subject of radiotracer development for application in nuclear oncology [3][4][5][6]. NT is a regulatory peptide present as a hormone in the gastrointestinal tract [7] and as a neurotransmitter in the central nervous system [8,9].…”

New neurotensin analogue radiolabeled by 99m‐technetium as a potential agent for tumor identification

“…We expect this spacer to decrease the influence of 99m-technetium metallic nature on the binding affinity of peptide and improve the pharmacokinetic of the new analogue. In this article, we describe the radiochemical and biological evaluation of a new radiolabeled NT analogue (5)(6)(7)(8)(9)(10)(11)(12)(13) Tc. This is significant because the radiolabeling of NT analogues with 99m Tc was mainly reported using the tricarbonyl approach and several new radiolabeled NT analogues with 99m Tc through bifunctional chelating agents such as MAG 3 , N 4 , and HYNIC.…”

“…[8] Because of the short halflife of NT in vivo (due to degradation by peptidases), there has been extensive research on the synthesis of an analogue of NT which has higher stability against peptidases (longer halflife) and also preserves its affinity to NTR1 and favorably uptakes by tumor. [9,10] For the synthesis of a new analogue, it should be considered that NT(8-13) sequences (Table 1) are necessary for new analogues to mimic the natural NT and these amino acids could not be omitted. [11] Metabolic deactivation of NT (8)(9)(10)(11)(12)(13) (Table 1).…”

“…[9,10] For the synthesis of a new analogue, it should be considered that NT(8-13) sequences (Table 1) are necessary for new analogues to mimic the natural NT and these amino acids could not be omitted. [11] Metabolic deactivation of NT (8)(9)(10)(11)(12)(13) (Table 1). [2] NT analogues are extensively labeled via various radionuclides like 18 F, 64 Cu, 68 Ga, 99 m Tc, and 111 In, and they are evaluated for the imaging of NT receptors' overexpression in different tumor types.…”

“…[2] NT analogues are extensively labeled via various radionuclides like 18 F, 64 Cu, 68 Ga, 99 m Tc, and 111 In, and they are evaluated for the imaging of NT receptors' overexpression in different tumor types. [9,[16][17][18][19] Among these radionuclides, labeling through 99m Tc due to favorite physical properties of radionuclide and abundant SPECT apparatus is preferred. So that NT analogue preserves its affinity to the receptor during the radiolabeling reaction, labeling should be performed through bifunctional chelating agents (BFCAs).…”