In vitro degradation of neurotensin in human plasma

Lee, Y.C.; Uttenthal, L. O.; Smith, Harry; Bloom, Stephen R.

doi:10.1016/0196-9781(86)90002-1

Cited by 16 publications

(11 citation statements)

References 22 publications

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“…However, a major metabolite peak at about 5 min was found for 18 F-FBEM-NT but not for 18 F-DEG-VS-NT. Nonetheless, because of the short half-life of NT in humans and rodents (39,40), a conclusion cannot be drawn based on just the above experiments. In a further approach, we have conjugated the more metabolically stable c(RGDyC) peptide with both synthons and studied the urine metabolism of 18 F-FBEM-c(RGDyC) and 18 F-DEG-VSc(RGDyC).…”

Section: Discussionmentioning

confidence: 86%

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

Liu

et al. 2014

J Nucl Med

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Accumulating evidence suggests that neurotensin receptors (NTRs) play key roles in cancer growth and survival. In this study, we developed a simple and efficient method to radiolabel neurotensin peptide with 18 F for NTR-targeted imaging. Methods: The thiolreactive reagent 18 F-(2-(2-(2-fluoroethoxy)ethoxy)ethylsulfonyl)ethane ( 18 F-DEG-VS) was facilely prepared through 1-step radiofluorination. After high-pressure liquid chromatography purification, 18 F-DEG-VS was incubated with the c(RGDyC) and c(RGDyK) peptide mixture to evaluate its specificity toward the reactive thiol. Thiolated neurotensin peptide was then labeled with 18 F using this novel synthon, and the resulting imaging probe was subjected to receptor-binding assay and small-animal PET studies in a murine xenograft model. The imaging results and metabolic stability of 18 F-DEG-VS-NT were compared with the thiol-specific maleimide derivative N-[2-(4-18 F-fluorobenzamido) ethyl]maleimide-neurotensin ( 18 F-FBEM-NT). Results: 18 F-DEG-VS was obtained in high labeling yield. The reaction of 19 F-DEG-VS was highly specific for thiols at neutral pH, whereas the lysine of c(RGDyK) reacted at a pH greater than 8.5. 18 F-DEG-VS-c(RGDyC) was the preferred product when both c(RGDyK) and c(RGDyC) were incubated together with 18 F-DEG-VS. Thiolated neurotensin peptide (Cys-NT) efficiently reacted with 18 F-DEG-VS, with a 95% labeling yield (decay-corrected). The radiochemical purity of the 18 F-DEG-VS-NT was greater than 98%, and the specific activity was about 19.2 ± 4.3 TBq/mmol. Noninvasive small-animal PET demonstrated that 18 F-DEG-VS-NT had an NTR-specific tumor uptake in subcutaneous HT-29 xenografts. The tumor-to-muscle, tumor-to-liver, and tumor-to-kidney ratios reached 30.65 ± 22.31, 11.86 ± 1.98, and 1.91 ± 0.43 at 2 h after injection, respectively, based on the biodistribution study. Receptor specificity was demonstrated by blocking experiment. Compared with 18 F-FBEM-NT, 18 F-DEG-VS-NT was synthesized with fewer steps and provided significantly improved imaging quality in vivo. Conclusion: We have established a facile 18 F-labeling method for site-specific labeling of the Cys-NT. Using this method, we synthesized an NTR-targeted PET agent, which demonstrated high tumor-to-background contrast.

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Section: Discussionmentioning

confidence: 86%

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

Liu

et al. 2014

J Nucl Med

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“…The concentration of SP could be lowered, because 3.13 μg/mL had the same effect as 25 μg/mL (Figure ). However, both NT and SP have a short half‐life and are enzymatically cleaved, which could argue for using a higher concentration to ensure that the peptides reach their target …”

Section: Discussionmentioning

confidence: 96%

“…However, both NT and SP have a short half-life and are enzymatically cleaved, which could argue for using a higher concentration to ensure that the peptides reach their target. 34 Combining NT and SP peptides did not increase their ability to increase wound closure, and surprisingly, the peptide combinations caused lower wound closure compared to the use of a single peptide The scratch assay is a very simple model to evaluate the peptide effect on keratinocytes. A limitation of the scratch assay is that wound closure can depend on both migration as well as cellular proliferation.…”

Section: Wound Closurementioning

confidence: 99%

Neurotensin, substance P, and insulin enhance cell migration

Mouritzen

Abourayale

Ejaz

et al. 2018

Journal of Peptide Science

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Neurotensin, substance P, and insulin have been demonstrated to improve wound healing in vivo. However, the mechanism behind their effect is still not fully understood. This study investigates the effects leading to enhanced scratch closure by these peptides in vitro. The skin keratinocyte cell line, HaCaT, was used to test scratch closure effects of the peptides and alterations of cytokine levels. HUVEC cells were used to test the angiogenic effect of the peptides. Furthermore, clinical isolates of Staphylococcus lugdunensis were used to examine the potential antimicrobial activity of each peptide. Our results demonstrate that neurotensin, substance P, and insulin had significant migratory effects in scratch assays were neurotensin had the lowest effect. Furthermore, we investigated use of the peptides in combination. When substance P was used in combination with neurotensin, the cell migratory capacity was decreased, and the peptides showed a negative correlation (r = -0.298, P < .001). Neurotensin and insulin significantly increased levels of monocyte chemoattractant protein-1 (P < .001) secreted from white blood cells, whereas substance P showed a tendency. Interestingly, neurotensin increased the level of monocyte chemoattractant protein-1 significantly compared to substance P (P < .01). Additionally, the peptides decreased TNFα mRNA levels (P < .001) in HaCaT cells, whereas only neurotensin and insulin decreased IL-8 mRNA (P < .001) but had no significant effect on IL-6 mRNA levels. Surprisingly, substance P increased IL-6 mRNA 9-fold (P < .001). Furthermore, we demonstrate that the peptides increased angiogenesis in the HUVEC cells (P < .001). Finally, S. lugdunensis isolates were not susceptible to the peptides. We demonstrate that the peptides worked differently on HaCaT cells, but substance P acted differently than neurotensin on cytokine levels expression as well as on migration of HaCaT cells. On the contrary, neurotensin and insulin worked similarly. All of these aspects are crucial for proper wound healing, and the results suggest multiple mechanisms for wound-healing properties of these peptides.

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“…The diffusion of NT to the surrounding structures is not probable, because NT is degraded by peptidases. The half life time of NT at 37 • C was measured 1.4 min in human plasma [51]. Electrophysiological studies proved that NT can modify the firing rate of dopaminergic neurons in the VTA and in the substantia nigra for more than 7 min [52].…”

Section: Discussionmentioning

confidence: 99%

Positive reinforcing effect of neurotensin microinjection into the ventral pallidum in conditioned place preference test

Ollmann

Péczely

László

et al. 2015

Behavioural Brain Research

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In vitro degradation of neurotensin in human plasma

Cited by 16 publications

References 22 publications

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

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

Neurotensin, substance P, and insulin enhance cell migration

Positive reinforcing effect of neurotensin microinjection into the ventral pallidum in conditioned place preference test

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In vitro degradation of neurotensin in human plasma

Cited by 16 publications

References 22 publications

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

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

Neurotensin, substance P, and insulin enhance cell migration

Positive reinforcing effect of neurotensin microinjection into the ventral pallidum in conditioned place preference test

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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

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