Neurotensin

A native 13-amino-acid peptide found in the brain and small intestine that signals through the NTS1 and NTS2 receptors and sortilin, studied in humans mainly as a physiology probe and never developed into an approved medicine.

Also referenced as: NT, NTS, NT(1-13), neurotensin acetate

Also appears in: Metabolic · Cognitive

COA Public product evidence No certificate records are bound to a tracked Neurotensin product page A record counts here only when a vendor publishes a certificate against one of its own tracked Neurotensin product pages. Other certificates naming this compound may still exist — search the wider certificate database. →

---

What is Neurotensin?

Neurotensin is a native tridecapeptide, a chain of 13 amino acids, that acts as a neurotransmitter in the brain and as a hormone in the gut. It was isolated from bovine hypothalami and first described as a new hypotensive peptide, the property that gave it its name (Carraway and Leeman, Journal of Biological Chemistry, 1973;248(19):6854–6861). Its sequence was established two years later as pyroGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu, with every residue unsubstituted and in the L configuration (Carraway and Leeman, Journal of Biological Chemistry, 1975;250(5):1907–1911). The molecular formula is C78H121N21O20 and the molecular weight is 1,672.9 Da. The C-terminal hexapeptide, neurotensin(8-13), carries the receptor-activating activity, and most analogs are built from it.

Neurotensin is cut from a precursor that also yields the hexapeptide neuromedin N and a stable 117-residue fragment, proneurotensin, which circulates in equimolar amounts and is what clinical laboratories measure. The peptide is concentrated in enteroendocrine cells of the small intestine, where fat ingestion releases it, and in dopamine-rich regions of the brain. No neurotensin product has ever been approved, and the programs built around its receptors use modified analogs or small molecules instead of the native peptide.

How it works

• High-affinity NTS1 receptor. NTS1 (NTSR1) was cloned from rat brain as a 424-residue G protein-coupled receptor that binds neurotensin selectively and desensitizes with repeated exposure (Tanaka et al., Neuron, 1990;4(6):847–854). A 2.8 Å crystal structure of rat NTSR1 bound to neurotensin(8-13) showed the peptide in an extended conformation nearly perpendicular to the membrane with its C-terminus pointed into the receptor core (White et al., Nature, 2012;490(7421):508–513). NTS1 knockout mice lose the hypothermia of 5 to 6 °C, the hot-plate analgesia and the gut smooth-muscle responses that neurotensin produces in wild-type animals, which places most of the classic pharmacology on this receptor (Pettibone et al., Journal of Pharmacology and Experimental Therapeutics, 2002;300(1):305–313).
• A low-affinity NTS2 receptor with unusual pharmacology. NTS2 (NTSR2), cloned from mouse brain, is a 417-residue GPCR with 39% homology to NTS1 that is also activated by the antihistamine levocabastine (Mazella et al., Journal of Neuroscience, 1996;16(18):5613–5620). At the human NTS2 in Chinese hamster ovary cells, neurotensin triggered no second-messenger response and instead antagonized the NTS1 antagonists SR48692 and SR142948A, which behaved as NTS2 agonists (Vita et al., European Journal of Pharmacology, 1998;360(2-3):265–272).
• Sortilin as a third binding site. The 100 kDa neurotensin-binding protein from human brain was identified as gp95/sortilin, an 833-residue non-GPCR that binds neurotensin with an affinity of 10 to 15 nM (Mazella et al., Journal of Biological Chemistry, 1998;273(41):26273–26276). Sortilin, together with NTS1, mediates the peptide’s stimulation of intestinal fatty acid absorption (Li et al., Nature, 2016;533(7603):411–415).
• Dopamine modulation and feeding. Neurotensin neurons and receptors are interwoven with the midbrain dopamine projections to the striatum, the basis for its long-standing label as an endogenous neuroleptic (Binder et al., Pharmacological Reviews, 2001;53(4):453–486). Peripherally injected neurotensin reduces food intake in mice and rats through an action blocked by a receptor antagonist, and the effect persists, though more briefly, after vagotomy (Ratner et al., Endocrinology, 2016;157(9):3482–3492).

Research status

Classic pharmacology. Intracisternal neurotensin produced hypothermia and intolerance to cold, the effect that later became the main liability of its analogs (Bissette et al., Nature, 1976;262(5569):607–609).

Human infusion studies. Synthetic neurotensin was infused into five healthy adults at 2.3 pmol/kg per minute for 30 minutes, raising plasma neurotensin to 104 pmol/L. The disappearance half-time was 3.8 minutes, metabolic clearance was 16 mL/kg per minute, plasma pancreatic polypeptide rose, and, in contrast to animal data, pulse, blood pressure, blood glucose, insulin, glucagon and pituitary hormones did not change (Blackburn et al., Journal of Clinical Endocrinology and Metabolism, 1980;51(6):1257–1261). In 12 volunteers infused at 2.4 pmol/kg per minute, the same group recorded inhibition of gastric acid and pepsin output and delayed gastric emptying of an oral glucose load (Blackburn et al., Lancet, 1980;1(8176):987–989). Four decades later, the University of Copenhagen registered three physiology studies of intravenous neurotensin: NCT03522792 (appetite, glucose regulation and in vivo degradation in an estimated 18 participants, started January 5, 2018, registry status unknown), NCT04179331 (appetite, hormone secretion and cardiovascular responses in 9 healthy volunteers, started March 1, 2019 and completed January 23, 2020) and NCT04186026 (co-infusion with GLP-1 in an estimated 35 adults with obesity, started October 1, 2019, registry status unknown). None has posted results.

Receptor antagonist studies in humans. The NTS1 antagonist SR48692 (meclinertant) reached human testing but not an approval. In a double-blind crossover study of 24 healthy men, single doses of 90 and 300 mg had no effect on esophageal motility or acid exposure even though meals raised plasma neurotensin as expected (Zerbib et al., Alimentary Pharmacology and Therapeutics, 2004;19(8):931–939), and in an exploratory placebo-controlled study in 24 patients with Parkinson disease it was well tolerated but did not improve parkinsonian motor disability (Mesnage et al., Clinical Neuropharmacology, 2004;27(3):108–110).

Psychiatric biomarker work. Among 42 drug-free patients with schizophrenia or schizoaffective disorder, those with the lowest cerebrospinal fluid neurotensin had the most severe psychopathology, and in 18 patients remeasured after 4 weeks of antipsychotic treatment, improvement correlated with rising CSF neurotensin (Sharma et al., American Journal of Psychiatry, 1997;154(7):1019–1021). Agonist programs followed this line of evidence.

Cardiometabolic biomarker. In 4,632 fasting participants of the Malmö Diet and Cancer Study examined between 1991 and 1994 and followed to January 2009, each standard-deviation increase in log proneurotensin carried a hazard ratio of 1.28 for incident diabetes, 1.17 for cardiovascular disease and 1.29 for cardiovascular mortality, with the associations concentrated in women, who also showed a hazard ratio of 1.44 for breast cancer (Melander et al., JAMA, 2012;308(14):1469–1475). Neurotensin-deficient mice absorb less intestinal fat and are protected from diet-induced obesity, and in non-obese people high proneurotensin marked a doubling of the risk of later obesity (Li et al., Nature, 2016;533(7603):411–415).

Analog programs, all preclinical. PD149163, a brain-penetrating NTS1-selective analog of neurotensin(8-13), reversed amphetamine-induced locomotion in rats without tolerance over eight daily injections (Feifel et al., Psychopharmacology, 2008;200(2):197–203) and reduced food intake and body weight in rats and ob/ob mice over 10 days, with hypothermia that waned while the anorectic effect did not (Feifel et al., Neuropharmacology, 2010;58(1):195–198). NT69L, an analog of neurotensin(8-13) containing N-methyl-arginine, L-neo-tryptophan and tert-leucine, produced hypothermia lasting more than 7 hours and hot-plate analgesia within 15 minutes after peripheral dosing (Tyler-McMahon et al., European Journal of Pharmacology, 2000;390(1-2):107–111) and attenuated intravenous nicotine self-administration in rats (Boules et al., Neuropeptides, 2011;45(1):9–16). NT79, designed for NTS2 selectivity, blocked acetic acid-induced writhing with an ED50 of 0.14 µg/kg and caused no significant hypothermia or blood pressure change (Boules et al., Brain Research, 2010;1308:35–46). None of these peptides has entered a registered human trial. The beta-arrestin-biased NTSR1 allosteric modulator SBI-553 attenuated addictive behaviors in mice without the side effects of balanced NTSR1 agonism (Slosky et al., Cell, 2020;181(6):1364–1379), and its analog SBI-810 relieved postoperative, inflammatory and neuropathic pain in rodents through NTSR1 and beta-arrestin-2 (Guo et al., Cell, 2025;188(16):4332–4349). As of November 2026, no registered human trial of either compound exists.

Receptor-targeted radiopharmaceuticals. The NTS1 receptor, not the peptide, has been the clinical target. 177Lu-3BP-227, a radiolabeled NTS1 antagonist, was given to six patients with end-stage pancreatic ductal adenocarcinoma; kidneys were the dose-limiting organ, the worst adverse event was reversible grade 2 anemia, and one patient had a partial response and lived 11 months from the start of treatment (Baum et al., Journal of Nuclear Medicine, 2018;59(5):809–814). The first-in-human phase 1/2 study (NCT03525392, as 177Lu-IPN01087) enrolled 14 participants between May 3, 2018 and April 28, 2021 and was terminated for reasons the registry records as unrelated to safety; results are posted on the registry. The actinium-225 successor [225Ac]-FPI-2059 entered a phase 1 trial on February 7, 2023 (NCT05605522, 19 participants) that was terminated for sponsor reprioritization. A new alpha-emitting NTSR1 program, SKL35501 with the imaging agent SKL35502 (NCT07812805), began a phase 1 study on August 19, 2026 in up to 100 patients with NTSR1-positive solid tumors, with primary completion estimated for July 2030. A six-patient academic study of the neurotensin-derived PET tracer 68Ga-DOTA-NT-20.3 (NCT05048810) completed on March 1, 2023 without posted results, and an 18F-labeled neurotensin PET study in prostate cancer (NCT03516045) and a Brazilian trial of neurotensin-loaded silk fibroin membranes for palatal wounds (NCT05191082) are listed with unknown status.

Regulatory record. Drugs@FDA lists no application for neurotensin, and no approved product label exists. As of November 2026, the native peptide has never been developed into an approved medicine in the US or elsewhere.

Common dosage forms

• Research reagent. Synthetic neurotensin is supplied as a lyophilized powder, usually as the acetate or trifluoroacetate salt, in vials labeled for laboratory use only.
• Clinical-study infusion material. The human physiology studies used synthetic neurotensin prepared under research protocols as a sterile solution for intravenous infusion, supplied only to the investigating hospital.
• No pharmaceutical presentation. No tablet, pen, ampoule, nasal spray or compounded preparation of neurotensin exists in any market.

Key considerations

• Regulatory status. The Research Market status reflects the absence of any FDA application, approved product or registered approval-directed trial of neurotensin in the US or abroad. The only clinical programs touching the target are academic physiology infusions and NTSR1-directed radioligands, none of which develops neurotensin itself.
• Human exposure is brief and well tolerated at physiological levels. Infusions that raised plasma neurotensin to about 104 pmol/L slowed gastric emptying and suppressed acid secretion without changing pulse or blood pressure, and the peptide disappeared with a half-time under 4 minutes. The hypotension, hypothermia and analgesia of its animal pharmacology require central administration or brain-penetrating analogs, none of which has been tested in people.
• Hypothermia and hypotension are the barrier to agonist drugs. The NTS1 agonists that reached animal testing, including PD149163 and NT69L, produced marked hypothermia, the stated reason the field moved toward NTS2-selective peptides such as NT79 and beta-arrestin-biased modulators such as SBI-553. The rodent data have not been followed by a single registered human trial of any analog.
• High proneurotensin is a risk marker, not a treatment. Proneurotensin predicts incident diabetes, cardiovascular disease and, in women, breast cancer, and mouse genetics tie the peptide to fat absorption and diet-induced obesity. Those findings give no support to supplementing the peptide.
• Naming. Neurotensin, NT, NTS and NT(1-13) denote the same peptide, and neurotensin(8-13) is its active fragment. PD149163, NT69L, NT79, SBI-553, SBI-810, 3BP-227, FPI-2059 and SKL35501 act at neurotensin receptors and are not aliases of neurotensin.