Neurotensin
NT, NTS gene product, pGlu-LYENKPRRPYIL
Neurotensin is a 13-residue peptide found in brain and in enteroendocrine N cells of the small intestine, isolated in 1973 from bovine hypothalamus during the purification of substance P. It acts at NTSR1, NTSR2 and the sorting receptor sortilin, with roles in analgesia, thermoregulation, dopamine modulation and fat absorption. Therapeutic development has repeatedly failed.
Mechanism
Neurotensin is cleaved from a precursor that also yields neuromedin N. NTSR1 and NTSR2 are class A GPCRs; NTSR1 couples chiefly to Gq/11, activating phospholipase C and raising intracellular calcium, while NTSR3, better known as sortilin, is a single-transmembrane VPS10-domain protein that traffics the peptide rather than signalling conventionally. Only the C-terminal region is required for receptor activation, so NT(8-13) is the pharmacophore used in nearly all analogue design, and the pyroglutamate N-terminus of the full peptide slows aminopeptidase attack.
Centrally, neurotensin is intimately linked to dopamine: it is co-localised with dopamine in mesolimbic projections, and central administration produces effects resembling antipsychotic drugs, including reduced locomotor response to psychostimulants. It also produces potent, naloxone-insensitive analgesia through NTSR1 in the periaqueductal grey and rostral ventromedial medulla, and profound hypothermia, the two effects being difficult to separate pharmacologically. Peripherally, gut-derived neurotensin slows gastric emptying and facilitates fatty acid absorption, and elevated pro-neurotensin has been associated in cohort studies with incident diabetes, cardiovascular disease and breast cancer.
What the research shows
Neurotensin has been infused in humans in physiological studies showing hypotension, flushing and effects on gastrointestinal motility, but these are old, small and not therapeutic. The most concrete recent human work targets the receptor rather than mimicking the peptide: lutetium-177-labelled 3BP-227, an NTSR1-targeted radioligand, was given to six patients with heavily pretreated ductal pancreatic adenocarcinoma. It was tolerated, the kidney was the dose-limiting organ, and one patient achieved a partial response with symptomatic improvement, surviving 11 months from the start of therapy. A follow-on study of the same agent, also designated 177Lu-IPN01087, was registered to extend this to other NTSR1-expressing solid tumours; that trial is recorded as terminated and no results publication has been located.
The negative record is substantial. Brain-penetrant neurotensin analogues developed as non-dopaminergic antipsychotics were derailed by hypothermia and hypotension, which track closely with the desired central effects. No neurotensin-based analgesic has reached late-stage trials, largely because separating analgesia from thermoregulatory collapse has proven intractable in animal models. Observational associations between pro-neurotensin and metabolic disease are consistent but do not establish causation or a treatment target.
Evidence assessment
Limited evidence
Human data comprise old physiological infusion studies and a first-in-human radioligand series of six patients targeting NTSR1 in pancreatic cancer. The follow-on trial of the same radioligand was registered as phase 1 and its registration status is terminated. No controlled therapeutic trial of neurotensin or a neurotensin agonist has succeeded.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami Preclinical only
Original isolation and naming of neurotensin, discovered incidentally during substance P purification and characterised by its vasodilator and hypotensive activity.
177Lu-3BP-227 for Neurotensin Receptor 1-Targeted Therapy of Metastatic Pancreatic Adenocarcinoma: First Clinical Results Preclinical only
Tolerated with kidney as dose-limiting organ; one partial response with symptomatic improvement. Six patients, no control group; hypothesis-generating only.
Study to Evaluate the Safety and Activity (Including Distribution) of 177Lu-3BP-227 in Subjects With Solid Tumours Expressing Neurotensin Receptor Type 1 Preclinical only
Sought to extend NTSR1-targeted radioligand therapy to a broader solid tumour population. The trial is recorded as terminated and no results publication has been located.
Safety
Neurotensin is not a licensed medicine. Human infusion causes hypotension, flushing and gastrointestinal effects. The dominant preclinical hazard is profound hypothermia at analgesic doses. Radioligand approaches carry renal dose-limiting toxicity. There is no safety database for repeated administration of the peptide in humans and no legitimate consumer use.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | No UK marketing authorisation. Unlicensed substance with no lawful supply route for human consumption. |
| United States | No FDA-approved neurotensin product. NTSR1-targeted radioligands remain investigational. Peptide material is a research reagent, not for human use. |
| WADA (sport) | Not individually named on the Prohibited List. Prohibited at all times under section S0 as a non-approved substance. |
Questions
Because the analgesia cannot be separated from profound hypothermia and hypotension. Both effects run through the same receptor populations in animal models, and no analogue has broken that link well enough to justify clinical trials.
NTSR1 is overexpressed in several tumours, particularly pancreatic adenocarcinoma, which is why radiolabelled NTSR1 ligands have been tested. The human data amount to a six-patient series and a follow-on trial that was terminated, not established treatment.