Peptide backbone modifications on the C-terminal hexapeptide of neurotensin

Einsiedel, Jürgen; Hübner, Harald; Hervet, Maud; Härterich, Steffen; Koschatzky, Susanne; Gmeiner, Peter

doi:10.1016/j.bmcl.2008.01.110

Cited by 34 publications

(31 citation statements)

References 38 publications

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“…Our plan of synthesis was based on our previous publications on metabolically stabilized NT(8–13) derivatives (Scheme 1) [7,28,29]. …”

Section: Resultsmentioning

confidence: 99%

“…The biologically active sequence is the C-terminal part NT(8–13) (Arg-Arg-Pro-Tyr-Ile-Leu) [2] which binds to the three neurotensin receptor subtypes NTS1, NTS2, NTS3 [3] and has therefore been selected as a lead structure for medicinal chemists [4,5,6,7,8,9,10,11,12,13]. The NTS1 is upregulated in various tumor types including prostate, pancreas, mamma, lung and colon carcinoma [14,15,16].…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Monitoring of the Antiangiogenic Effect of Neurotensin Receptor-Mediated Radiotherapy by Small-Animal Positron Emission Tomography: A Pilot Study

et al. 2014

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The neurotensin receptor (NTS1) has emerged as an interesting target for molecular imaging and radiotherapy of NTS-positive tumors due to the overexpression in a range of tumors. The aim of this study was to develop a 177Lu-labeled NTS1 radioligand, its application for radiotherapy in a preclinical model and the imaging of therapy success by small-animal positron emission tomography (µPET) using [68Ga]DOTA-RGD as a specific tracer for imaging angiogenesis. The 177Lu-labeled peptide was subjected to studies on HT29-tumor-bearing nude mice in vivo, defining four groups of animals (single dose, two fractionated doses, four fractionated doses and sham-treated animals). Body weight and tumor diameters were determined three times per week. Up to day 28 after treatment, µPET studies were performed with [68Ga]DOTA-RGD. At days 7–10 after treatment with four fractionated doses of 11–14 MBq (each at days 0, 3, 6 and 10), the tumor growth was slightly decreased in comparison with untreated animals. Using a single high dose of 51 MBq, a significantly decreased tumor diameter of about 50% was observed with the beginning of treatment. Our preliminary PET imaging data suggested decreased tumor uptake values of [68Ga]DOTA-RGD in treated animals compared to controls at day 7 after treatment. This pilot study suggests that early PET imaging with [68Ga]DOTA-RGD in radiotherapy studies to monitor integrin expression could be a promising tool to predict therapy success in vivo. Further successive PET experiments are needed to confirm the significance and predictive value of RGD-PET for NTS-mediated radiotherapy.

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“…Our plan of synthesis was based on our previous publications on metabolically stabilized NT(8–13) derivatives (Scheme 1) [7,28,29]. …”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In Vivo Monitoring of the Antiangiogenic Effect of Neurotensin Receptor-Mediated Radiotherapy by Small-Animal Positron Emission Tomography: A Pilot Study

et al. 2014

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“…b) Homologated Derivatives of 2a. Neurotensin(8 -13) analogs, 2d and 2e, which contain only one terminal b-amino acid residue have been described in [78]. We have now prepared the doubly homologated analogs 2b and 2c, bearing (R)-or (S)-b 2 hArg on the N-terminus and (S)-b 3 hLeu on the C-terminus.…”

Section: 1mentioning

confidence: 99%

“…NT2 Receptor binding was determined using preparations from HEK 293 cells transiently expressing the human NT2 and [ 3 H]NT(8 -13) [93]. All results were compared with the reference NT (1) and hexapeptide 2a [78]. The ability to displace [ 3 H]NT and [ 3 H]NT(8 -13) from the receptor was lower for both doubly homologated compounds compared to the native NT(8 -13) (2a; Table 1).…”

Section: 1mentioning

confidence: 99%

On the Terminal Homologation of Physiologically Active Peptides as a Means of Increasing Stability in Human Serum – Neurotensin, Opiorphin, B27‐KK10 Epitope, NPY

Seebàch

Lukaszuk

Patora-Komisarska

et al. 2011

Chemistry & Biodiversity

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The terminal homologation by CH(2) insertion into the peptides mentioned in the title is described. This involves replacement of the N-terminal amino acid residue by a β(2) - and of the C-terminal amino acid residue by a β(3) -homo-amino acid moiety (β(2) hXaa and β(3) hXaa, resp.; Fig. 1). In this way, the structure of the peptide chain from the N-terminal to the C-terminal stereogenic center is identical, and the modified peptide is protected against cleavage by exopeptidases (Figs. 2 and 3). Neurotensin (NT; 1) and its C-terminal fragment NT(8-13) are ligands of the G-protein-coupled receptors (GPCR) NT1, NT2, NT3, and NT analogs are promising tools to be used in cancer diagnostics and therapy. The affinities of homologated NT analogs, 2b-2e, for NT1 and NT2 receptors were determined by using cell homogenates and tumor tissues (Table 1); in the latter experiments, the affinities for the NT1 receptor are more or less the same as those of NT (0.5-1.3 vs. 0.6 nM). At the same time, one of the homologated NT analogs, 2c, survives in human plasma for 7 days at 37° (Fig. 6). An NMR analysis of NT(8-13) (Tables 2 and 4, and Fig. 8) reveals that this N-terminal NT fragment folds to a turn in CD(3) OH. - In the case of the human analgesic opiorphin (3a), a pentapeptide, and of the HIV-derived B27-KK10 (4a), a decapeptide, terminal homologation (→3b and 4b, resp.) led to a 7- and 70-fold half-life increase in plasma (Fig. 9). With N-terminally homologated NPY, 5c, we were not able to determine serum stability; the peptide consisting of 36 amino acid residues is subject to cleavage by endopetidases. Three of the homologated compounds, 2b, 2c, and 5c, were shown to be agonists (Fig. 7 and 11). A comparison of terminal homologation with other stability-increasing terminal modifications of peptides is performed (Fig. 5), and possible applications of the neurotensin analogs, described herein, are discussed.

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“…This modification can lead to a dramatic increase of plasma stability (see, e.g., the data for NTS derivatives 1 -4 ( Table 1)), without loss of affinity for the receptor(s) [6]. The next, more stringent requirement for an application 7 ) of a G-protein-coupled receptor (GPCR)-targeting peptide [10] is the attachment of a metal-ion chelating moiety 8 ) or of a 18 F-containing group 9 ), in such a way that the receptor-binding affinity is not substantially decreased.…”

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confidence: 98%

Syntheses, Receptor Bindings, in vitro and in vivo Stabilities and Biodistributions of DOTA‐Neurotensin(8–13) Derivatives Containing β‐Amino Acid Residues – A Lesson about the Importance of Animal Experiments

Sparr

Purkayastha

Yoshinari

et al. 2013

Chemistry & Biodiversity

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Neurotensin(8-13) (NTS(8-13)) analogs with C- and/or N-terminal β-amino acid residues and three DOTA derivatives thereof have been synthesized (i.e., 1-6). A virtual docking experiment showed almost perfect fit of one of the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) derivatives, 6a, into a crystallographically identified receptor NTSR1 (Fig.1). The affinities for the receptors of the NTS analogs and derivatives are low, when determined with cell-membrane homogenates, while, with NTSR1-exhibiting cancer tissues, affinities in the single-digit nanomolar range can be observed (Table 2). Most of the β-amino acid-containing NTS(8-13) analogs (Table 1 and Fig.2), including the (68) Ga complexes of the DOTA-substituted ones (6; Figs.2 and 5), are stable for ca. 1 h in human serum and plasma, and in murine plasma. The biodistributions of two (68) Ga complexes (of 6a and 6b) in HT29 tumor-bearing nude mice, in the absence and in the presence of a blocking compound, after 10, 30, and 60 min (Figs. 3 and 4) lead to the conclusion that the amount of specifically bound radioligand is rather low. This was confirmed by PET-imaging experiments with the tumor-bearing mice (Fig.6). Comparison of the in vitro plasma stability (after 1 h) with the ex vivo blood content (after 10-15 min) of the two (68) Ga complexes shows that they are rapidly cleaved in the animals (Fig.5).

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Peptide backbone modifications on the C-terminal hexapeptide of neurotensin

Cited by 34 publications

References 38 publications

In Vivo Monitoring of the Antiangiogenic Effect of Neurotensin Receptor-Mediated Radiotherapy by Small-Animal Positron Emission Tomography: A Pilot Study

In Vivo Monitoring of the Antiangiogenic Effect of Neurotensin Receptor-Mediated Radiotherapy by Small-Animal Positron Emission Tomography: A Pilot Study

On the Terminal Homologation of Physiologically Active Peptides as a Means of Increasing Stability in Human Serum – Neurotensin, Opiorphin, B27‐KK10 Epitope, NPY

Syntheses, Receptor Bindings, in vitro and in vivo Stabilities and Biodistributions of DOTA‐Neurotensin(8–13) Derivatives Containing β‐Amino Acid Residues – A Lesson about the Importance of Animal Experiments

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