PT-141 10mg Peptide

PT-141 is the development code for bremelanotide, a synthetic cyclic heptapeptide analogue of alpha-melanocyte-stimulating hormone that acts as an agonist at melanocortin receptors. Its sequence is Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH, closed by a side-chain lactam bridge between the aspartate at position 1 and the lysine at position 7. The free base is C50H68N14O10 at 1,025.2 g/mol, CAS 189691-06-3, PubChem CID 9941379.

The compound came out of Melanotan II research at Palatin Technologies in the late 1990s. Melanotan II carries a C-terminal carboxamide; PT-141 is the same macrocycle with that amide hydrolysed to the free acid, which is why the older literature describes it as the active metabolite of MT-II rather than a separate scaffold. Both compounds sit in this catalogue, and the difference between them is a single functional group.

PT-141 has an unusually complete public record for a research peptide. It ran through 43 completed studies covering roughly 3,500 subjects across phases 1 to 3, produced two identical Phase 3 trials known as RECONNECT, received United States marketing authorisation under the brand name Vyleesi in June 2019, and had an earlier intranasal formulation abandoned over blood pressure and exposure-variability findings. It also carries an active research programme well outside sexual function, including a completed Phase 2b renal study and an ongoing obesity combination study.

PT-141 is a non-selective melanocortin agonist, not an MC4R-specific ligand. Ranked by potency in receptor panels it engages MC1R first, then MC4R, MC3R, MC5R and MC2R. What makes MC4R the pharmacologically interesting receptor is not selectivity but exposure: at the plasma concentrations reached in the clinical programme, MC4R is the subtype considered most relevant, and MC4R is densely expressed in the medial preoptic area of the hypothalamus.

The central rather than vascular site of action was established early. Molinoff and colleagues reported in 2003 that systemic PT-141 produced penile erections in rats and in non-human primates, and raised c-Fos immunoreactivity in hypothalamic neurons. The same hypothalamic region takes up pseudorabies virus delivered to the rat corpus cavernosum, which traced an anatomical route from those activated neurons to the periphery. This is a different pharmacology from a PDE5 inhibitor, which acts on peripheral vascular smooth muscle downstream of nitric oxide signalling.

The proposed downstream step is dopaminergic. A 2022 review by Pfaus and colleagues sets out the model in which presynaptic MC4R activation in the medial preoptic area increases dopamine release. That model is not settled. A 2025 female Syrian hamster study mapped MC3R and MC4R mRNA and found most of it in ventral tegmental area dopamine neurons, with the nucleus accumbens signal sitting on interneurons rather than on D1 or D2 receptor neurons. Neither the low nor the high dose changed melanocortin receptor mRNA in that pathway, and bremelanotide did not enhance conditioned place preference for sexual experience. The authors concluded that the compound does not act through the VTA to nucleus accumbens reward circuit.

Melanotan II is Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2, C50H69N15O9, 1,024.2 g/mol, PubChem CID 92432. PT-141 is the identical macrocycle with the C-terminal lysine carboxamide hydrolysed to the free acid: one NH traded for one O, giving C50H68N14O10 at 1,025.2 g/mol. That single change is the whole structural difference between the two compounds, and it is why the early literature calls bremelanotide the active metabolite of MT-II rather than a new molecule.

The lineage runs through a 1998 J Urol study in which 10 men with psychogenic erectile dysfunction received Melanotan II at 0.025 mg/kg in a double-blind placebo-controlled crossover. Eight of ten developed clinically apparent erections, and mean duration of tip rigidity above 80 percent was 38.0 minutes against 3.0 minutes on placebo (p=0.0045). Nausea, stretching, yawning and reduced appetite were more frequent than on placebo. That result is what motivated the search for the metabolite responsible for the arousal effect, separate from the pigmentation effect MT-II had been designed for.

The one-dalton difference is not academic. An Italian forensic toxicology laboratory characterising eight confiscated black-market samples in 2021 had to separate the two using Orbitrap LC-HRMS, working from accurate mass of the MH+ ion, relative isotopic abundance and the accurate masses of collision-induced product ions. A nominal-mass method cannot reliably distinguish a 1,024 Da amide from a 1,025 Da acid. Any identity claim for PT-141 that rests on unit-resolution mass spectrometry is not distinguishing it from its parent.

The standard claim in this category is that PT-141 does not tan the skin because it lacks MC1R activity. Receptor panels do not support the second half of that sentence. Ranked by potency, bremelanotide is an agonist at MC1R before MC4R. The compound is non-selective across the melanocortin family and MC1R sits at the top of the list.

What the safety review across the full development programme found is that pigmentation tracks the exposure schedule, not receptor selectivity. Reviewing 43 completed studies across roughly 3,500 subjects, Clayton and colleagues reported in 2022 that focal hyperpigmentation was rare when the compound was given on the intermittent schedule used in the Phase 3 trials, but occurred in more than one third of subjects given up to 16 consecutive daily doses.

That is the honest version of the comparison with the Melanotan II record in this catalogue. Melanogenesis is a cumulative transcriptional response in melanocytes, and MT-II pigmentation research used repeated administration over days to weeks. An on-demand melanocortin agonist and a daily one produce different pigmentation outcomes from receptors both compounds engage. The difference between the two peptides in this respect is one of exposure pattern and relative MC1R engagement, not the presence or absence of MC1R agonism.

PT-141 was developed first as an intranasal spray, and that formulation did not survive. Diamond and colleagues reported the intranasal pharmacokinetics in 2004: median Tmax of 0.50 hours and mean elimination half-life between 1.85 and 2.09 hours in healthy men, with an erectile response by RigiScan reaching statistical significance only above 7 mg, roughly four times the exposure the later subcutaneous formulation required. Flushing and nausea dominated the adverse event profile and no maximum tolerated dose was identified.

A larger intranasal trial followed in 2008: 342 men who had not responded to sildenafil received either 10 mg intranasal bremelanotide or placebo before sexual stimulation, with positive clinical results reported in 33.5 percent of the treated group. That paper carries an Expression of Concern issued by J Urol in January 2023 and should not be read as a settled result.

The reason the route was abandoned is stated plainly in the 2017 ambulatory blood pressure paper. The intranasal formulation was associated with wide variability in bioavailability, exposing some patients to plasma levels above what efficacy required while leaving others under-exposed. The upper tail of that distribution brought a heightened risk of autonomic effects, including elevations in blood pressure. A subcutaneous formulation was developed specifically to tighten the relationship between dose and exposure.

The regulatory consequence is recorded in the Phase 2b protocol. Blood pressure was monitored manually for two hours after each in-clinic administration and by 24-hour ambulatory monitoring at 15-minute intervals, and the paper states this intensive monitoring was included to address United States regulator concerns raised after the earlier intranasal studies. Prespecified withdrawal thresholds were systolic 150 to 170 mmHg or diastolic 95 to 105 mmHg across consecutive readings, or a change from baseline of 30 mmHg systolic or 15 mmHg diastolic.

What the monitoring found in 397 women is modest. At 1.75 mg, ambulatory systolic pressure rose 3.1 and 3.2 mmHg above placebo in the 0 to 4 hour window after two administrations 24 hours apart (P=0.006 and P=0.027), peaks typically lasted under 15 minutes, and the increase was accompanied by a heart rate fall of 4.6 to 4.7 bpm. Twenty-six participants were withdrawn for prespecified blood pressure increases, in similar proportions across all four arms including placebo. The signal is real, small and transient, and it is why the marketed product carries a caution in uncontrolled hypertension and known cardiovascular disease.

By the subcutaneous route, absolute bioavailability is reported at 100 percent, Tmax at 0.5 to 1.0 hours, and plasma half-life at 2.7 hours with a reported range of 1.9 to 4.0 hours. Mean volume of distribution is 25.0 plus or minus 5.8 L and mean clearance 6.5 plus or minus 1.0 L/h. In a radiolabelled study, 64.8 percent of the administered radioactivity was recovered in urine and 22.8 percent in faeces.

As a seven-residue peptide, bremelanotide is cleared by sequential hydrolysis rather than by cytochrome P450 metabolism. That is why the drug interaction work across the development programme was largely unremarkable, with the exceptions being reduced plasma concentrations of indomethacin and naltrexone, and why a Phase 1 ethanol coadministration study found no clinically significant interaction.

Exposure is dose-proportional. Mean Cmax was 37.5, 60.0 and 77.2 ng/mL at 0.75, 1.25 and 1.75 mg, with a Cmax range at 1.75 mg of 14.7 to 115.0 ng/mL on first administration. The intranasal comparison is instructive: the same median Tmax of about 0.5 hours, but a far shallower and more variable dose response, needing more than 7 mg to reach a measurable erectile endpoint.

Pharmacodynamic duration outlasts plasma concentration. The 2017 pharmacokinetic analysis found no relationship between maximal observed systolic pressure change and Cmax, and the authors attribute the disconnect to a central nervous system agonist remaining engaged on target tissue after systemic concentrations have fallen. A half-life figure alone is therefore a poor predictor of effect duration for this compound.

RECONNECT comprised two identically designed Phase 3 trials, NCT02333071 and NCT02338960, running from January 2015 to mid-2016 with 24 weeks of on-demand subcutaneous administration at 1.75 mg against placebo. Of 1,267 women randomised, 1,247 formed the safety population and 1,202 the modified intent-to-treat population. Participants had a mean age of 39, 85.6 percent were white, and 96.6 percent came from United States sites. The co-primary endpoints were change from baseline in the Female Sexual Function Index desire domain and in item 13 of the Female Sexual Distress Scale covering desire, arousal and orgasm.

Tolerability, not efficacy, dominates the safety picture. Across the integrated double-blind phase, nausea occurred in 40.0 percent against 1.3 percent on placebo, flushing in 20.3 percent against 1.3 percent, and headache in 11.3 percent against 1.9 percent. Nausea was the most common reason for discontinuation. A quieter number carries the same message: 70 percent of the bremelanotide group elected to continue into the open-label extension, against 87 percent of the placebo group.

The 52-week open-label extension enrolled 684 of the 856 women who completed the core phase, of whom 272 finished. No new safety signals emerged, and the desire and distress changes were sustained. Prespecified subgroup analyses across age, weight, body mass index and baseline bioavailable testosterone quartiles found the direction of effect consistent, with few exceptions.

The counter-literature deserves reading alongside the trial reports. A 2021 re-analysis in J Sex Res argued the Phase 3 effect sizes are small relative to the trials' own placebo response, drew a published reply defending the original analysis, and sits alongside a 2018 meta-analysis quantifying how large the placebo effect is in female sexual dysfunction trials generally. A 2023 review in Expert Opin Pharmacother describes the overall clinical benefit as modest while noting the genuine difficulty of designing trials whose outcome measures rely on long recall periods for sexual and emotional response. A page that reports only the P values is reporting half of what the literature says.

The melanocortin system reaches well past arousal, and the active bremelanotide programme reflects that. A Phase 2b open-label study in diabetic kidney disease (NCT05709444) enrolled 16 participants and completed in April 2024, measuring urinary protein reduction and podocyte density alongside renin-angiotensin-aldosterone system inhibition. The mechanistic basis is MC1R rather than MC4R: podocytes were identified in 2010 as the strongest MC1R expressers in the glomerulus, and a selective MC1R agonist significantly reduced proteinuria in rats with passive Heymann nephritis while improving podocyte morphology and lowering oxidative stress.

A Phase 2 randomised double-blind study of bremelanotide coadministered with tirzepatide in obesity (NCT06565611) enrolled an estimated 108 participants from August 2024 and is active but no longer recruiting. The premise is the MC4R satiety pathway that the two Phase 1 caloric-intake trials probed directly, paired with an incretin agonist acting through a separate mechanism.

Oncology work is at the cell-line stage. A 2024 Anticancer Research paper found that bremelanotide reduced survivin expression and induced death in human glioblastoma cell lines at concentrations that spared normal human cells, with both effects blocked by an MC3R and MC4R antagonist and rescued by forced survivin over-expression. The compound also increased cell death produced by temozolomide and osimertinib. This is an in vitro observation identifying MC3R and MC4R as candidate targets, not a therapeutic finding.

The 1,025.2 g/mol figure and CAS 189691-06-3 both describe the free base. Lyophilised peptide is almost always supplied as the acetate salt, so a certificate of analysis reporting net peptide content against the acetate mass will show a lower peptide fraction than a vial labelled by gross mass implies. This distinction is systematically absent from listings in this category, and it is the first thing to check when two certificates appear to disagree about content.

Purity and identity are different measurements answering different questions. Purity is an HPLC area percentage against the total chromatographic response; identity is a mass or sequence confirmation. A figure presented as purity by mass spectrometry conflates the two. For this compound the point matters more than usual, because the 1 Da separation from Melanotan II is not resolvable at unit resolution, so identity confirmation needs high-resolution accurate-mass data of the kind used in the 2021 forensic characterisation. An ultra-sensitive UHPLC-MS/MS assay for bremelanotide in plasma was published in 2020 for pharmacokinetic work requiring quantification below the ng/mL range.

Sequence notation is worth reading carefully. The unambiguous form is Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH. A linear seven-residue string omits the Asp1 to Lys7 side-chain lactam bridge that defines the macrocycle, and a string that drops the D-configuration at position 4 or the N-terminal norleucine describes a different molecule from the one the trial literature studied.

Reconstituted stability figures circulating in this category range from 7 to 30 days at 2 to 8 degrees Celsius, and none of the sources carrying them cite a study. No published stability data for bremelanotide in bacteriostatic water was located during this review. Lyophilised material stored cold and protected from light and moisture is the well-characterised state; anything asserted about the solution beyond that is an unsourced number and should be treated as one.