MT-2 (Melanotan II)

What MT-2 is

MT-2, written MT-II or Melanotan II in most of the primary literature, is a synthetic cyclic heptapeptide with the sequence Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2. It is an analogue of the central pharmacophore of α-melanocyte-stimulating hormone (α-MSH), the 13-residue hormone cleaved from pro-opiomelanocortin in the pituitary and the skin. The molecule was designed in Victor Hruby's laboratory at the University of Arizona, in collaboration with Mac Hadley's group there, and first reported in 1989 in a pair of papers in the Journal of the American Chemical Society and the Journal of Medicinal Chemistry [1, 2].

The design logic explains every unusual feature of the structure. Hruby's group had already shown that replacing the oxidation-prone methionine at position 4 of α-MSH with norleucine, and inverting the phenylalanine at position 7 to D-Phe, gave a linear analogue (Nle4, D-Phe7-α-MSH, later Melanotan I or afamelanotide) with much greater potency and resistance to enzymatic degradation. Quenched molecular dynamics simulations of that peptide suggested that the active conformation brought the side chains of residues 5 and 10 close together [1]. The group therefore trimmed the sequence to the 4–10 core, replaced Glu5 and Gly10 with aspartate and lysine, and joined their side chains through a lactam bridge. The resulting cyclic lactam was far more potent than α-MSH in the frog skin bioassay and showed prolonged activity in the lizard skin assay [1, 2]. This compound is MT-II.

Structurally, then, MT-2 is a seven-residue peptide with an acetylated N-terminus, an amidated C-terminus, two non-natural residues (norleucine and D-phenylalanine) and a side-chain-to-side-chain lactam between Asp2 and Lys7 that constrains the His-D-Phe-Arg-Trp core into a β-turn. There is no cysteine and no disulphide. The tryptophan is the one residue that calls for care at the bench: it is the principal chromophore and it is susceptible to oxidation and photodegradation. The reference identifiers are given in the table.

Research-grade MT-2 is a white to off-white lyophilised powder, supplied by BuyUK Peptides strictly as a reference compound for in-vitro laboratory work.

How the literature describes its mechanism

Unlike many peptides in a research catalogue, MT-2 has a well-defined target family. It is an agonist at the melanocortin receptors, five class A G-protein-coupled receptors (MC1R to MC5R) that couple through Gs to adenylyl cyclase and raise intracellular cyclic AMP. Their distribution differs: MC1R on melanocytes and some immune cells, MC2R in the adrenal cortex (where it responds to ACTH and not to the shorter melanotropins), MC3R and MC4R in the central nervous system, and MC5R in exocrine tissue including sebaceous glands.

The defining pharmacological feature of MT-2 is that it is not selective. When the cloned human receptors became available in the mid-1990s, Hruby and colleagues, with Roger Cone's laboratory, characterised MT-II and a series of position-7 analogues at hMC1R, hMC3R, hMC4R and hMC5R. MT-II was a potent full agonist at all four, whereas the D-Nal(2')7 substitution produced SHU9119, an antagonist at MC3R and MC4R that kept agonist activity at MC1R and MC5R [5]. MT-II as the non-selective agonist and SHU9119 as the matched antagonist have been the standard tools of melanocortin pharmacology for three decades, and much of what is known about MC3R and MC4R in rodents was first established with them.

For the in-vitro researcher this has two consequences. First, MT-2 is a reference agonist, not a probe: a response to it in a cell line shows that one or more melanocortin receptors are present and coupled, but not which; receptor identity has to come from subtype-selective ligands, antagonists or expression data. Second, the readout is well established. The canonical assay is cAMP accumulation in cells expressing a single receptor subtype, typically HEK293 or CHO transfectants, with low-nanomolar potencies at MC1R, MC3R, MC4R and MC5R [5]. In melanocytes and melanoma lines the downstream readouts are tyrosinase activity, eumelanin synthesis and pigmentation gene expression, driven through MC1R, cAMP and MITF.

The reported effects of MT-II in whole animals follow from that receptor profile. MC1R stimulation darkens pigment cells, which is why frog and lizard skin bioassays were used for the original structure–activity work [1, 2]. MC3R and MC4R activation in the hypothalamus is associated in rodents with reduced food intake and with penile erection, the latter first seen as an unexpected finding in the rat and then in humans [3, 6]. MC5R activation increases sebum production. None of this bears on in-vitro work except as context for what a cell-based assay is modelling.

The research record

The research history of MT-2 is two histories running in opposite directions: a careful academic and early-clinical programme that was discontinued, and an uncontrolled public-health episode that is still running.

Origin and early pharmacology. The 1989 design papers established that the cyclic lactam was more potent than the parent hormone and more resistant to degradation [1, 2]. Hadley and Dorr's 2006 review in Peptides, by two of the original investigators, is the most accessible account of what followed: the University of Arizona patented both Melanotan I and Melanotan II, licensed them through Competitive Technologies, and studied them in the early 1990s as potential agents for increasing eumelanin in fair skin as a form of photoprotection [3]. That rationale was the research question of its time and does not translate into any legitimate use of the material sold here.

The first human study. Dorr and colleagues published the pilot phase I study of MT-II in Life Sciences in 1996 [4], a small study in healthy male volunteers at the University of Arizona Cancer Center designed to establish tolerability and to see whether pigmentation could be induced. The paper reports skin darkening measured by reflectance, and it also reports the adverse effects that would define the compound's later reputation: nausea, facial flushing, yawning and stretching, fatigue, and spontaneous penile erections, the last consistent with central melanocortin signalling already seen in rats.

The sexual-function programme. The erectile observation redirected the clinical work. Wessells and colleagues at Arizona ran a double-blind, placebo-controlled crossover study in men with psychogenic erectile dysfunction in 1998, and a second in men with organic erectile dysfunction, published in Urology in 2000 [6]. The second paper reported erections in a majority of subjects after MT-II against a small minority after placebo, with increased desire scores, but also nausea and the other systemic effects seen in the phase I study. This is the work from which the melanocortin approach to sexual dysfunction derives [3, 6].

Why MT-II itself was not pursued. The clinical rights passed to Palatin Technologies in the late 1990s. Molinoff and colleagues at Palatin reported in 2003 that a metabolite of MT-II, the free-acid form in which the C-terminal amide is replaced by a carboxylic acid, retained melanocortin agonist activity with a cleaner profile in their hands; they designated it PT-141 [7]. Palatin stopped developing MT-II around 2000 in favour of PT-141, which became bremelanotide and was approved by the US FDA in 2019 for hypoactive sexual desire disorder in premenopausal women. The reasons were partly commercial and partly pharmacological: the free acid could be patented afresh, and the parent peptide's non-selectivity, nausea and flushing made it an unattractive candidate. Melanotan I became afamelanotide, a licensed medicine for erythropoietic protoporphyria [3]. MT-II has never been licensed, has no registered clinical development that we are aware of, and has had no controlled trial since the Arizona work.

The unregulated-use literature. From about 2007, MT-II began to be sold through websites and gyms as a "tanning injection", with no regulatory oversight and no quality control. Evans-Brown and colleagues at Liverpool John Moores University documented the phenomenon in a letter to the BMJ in 2009, describing melanotan products among people who injected image- and performance-enhancing drugs and at needle-exchange services in north-west England [8]. The MHRA issued public warnings in 2008 and 2009 and wrote to companies advertising the products that they were being sold illegally [9]. Habbema and colleagues reviewed the subsequent case literature in the International Journal of Dermatology in 2017 [10]. The reported associations include:

• Changes in melanocytic naevi. Cardones and Grichnik described eruptive naevi after use of an α-MSH analogue in 2009 [11], and later reports describe new, darkening and dysplastic naevi in users, the expected consequence of sustained MC1R stimulation and one that complicates skin surveillance.
• Melanoma. Ong and Bowling reported melanoma in situ in a user in 2012 [12], and Habbema's review collects further cases [10]. Whether the association is causal, a matter of pre-existing lesions becoming visible, or coincidence has not been established.
• Rhabdomyolysis and systemic toxicity. Nelson, Bryant and Aks described systemic toxicity with rhabdomyolysis after injection of a product sold as Melanotan II [13].
• Priapism. Dreyer and colleagues reported priapism requiring surgical intervention [14], an outcome predictable from the erectile pharmacology above.
• Renal injury. Peters and colleagues reported renal infarction and reviewed the literature [15].

Two features of this literature matter to a scientific reader. First, nearly all of it concerns products of unknown identity, purity and content. Breindahl and colleagues analysed melanotan products bought from the internet by LC-UV-MS/MS and found variable content, impurities and, in some vials, the wrong peptide altogether [16]. A case report attributed to "Melanotan II" is therefore a report about an unregulated injection, not a characterised compound at a known exposure. Second, none of it is controlled: the denominator is unknown and the attributions rest on temporal association. The case reports cannot establish causation, and nobody can offer any reassurance either. The compound has no human safety database beyond the small Arizona studies of the 1990s, which themselves recorded a consistent pattern of systemic effects [4, 6].

Taking the record as a whole. At the level of molecular pharmacology MT-2 is one of the best-characterised peptides in the catalogue, a standard reference agonist with measured potencies at cloned receptors [5]. At the level of human use it is a discontinued clinical candidate with a short and cautionary record, unlicensed everywhere, with fifteen years of case reports arising from its sale as a cosmetic injection. The first is a sound reason to hold it as a reference compound for in-vitro work. The others are why this page, and the Terms of Sale, say it is for nothing else.

Regulatory status in the United Kingdom

MT-2 is not licensed as a medicine in the UK or in any other jurisdiction. It has no marketing authorisation, no pharmacopoeial monograph and no approved use of any kind. BuyUK Peptides supplies it as a research chemical for in-vitro laboratory use under the Terms of Sale. It is not for human or veterinary administration. Purchasers must be 18 or over and are responsible for ensuring their use of the material complies with the laws and institutional rules that apply to them. Our guide to the UK rules on research compounds covers the general framework; the specific points for this compound are below.

The MHRA and "tanning injections". The Medicines and Healthcare products Regulatory Agency has taken a clear public position on Melanotan since 2008: the products marketed as tanning injections are unlicensed medicines, they have not been assessed for safety, quality or efficacy, selling or advertising them for that purpose is illegal, and the agency wrote to the companies doing so requiring them to stop [9]. The researchers who first documented UK use, writing in the BMJ, likewise called for the products to be recognised as a public-health problem [8].

Why the purpose of supply is the legal hinge. Under the Human Medicines Regulations 2012, which consolidate the former Medicines Act provisions, a product is a medicinal product if it is presented as treating or preventing disease, or if it may be administered to humans to restore, correct or modify a physiological function, and a medicinal product cannot be sold, supplied or advertised without a marketing authorisation. A substance marketed as something to inject to darken the skin or alter sexual function falls within that definition whatever the seller calls it, which is the basis on which the MHRA acts against sellers of tanning injections. The same substance, supplied as a reference standard for laboratory research with no claim or suggestion of human use, is not presented as a medicinal product and is governed by the general law on chemicals. The distinction is one of purpose and presentation, not chemistry, which is why this page, the product page and the Terms of Sale are explicit that the material is for in-vitro research only. A buyer who intends to administer it to a person is outside the Terms of Sale; a seller who markets it for that purpose is committing an offence.

Anti-doping. MT-2 is not named individually on the World Anti-Doping Agency Prohibited List. The List's S0 category, however, covers any pharmacological substance not approved by any governmental regulatory health authority for human therapeutic use, and a non-approved melanocortin agonist falls within that description. Researchers at institutions subject to anti-doping rules should treat it as prohibited at all times under S0.

Handling, storage and stability

MT-2 is supplied lyophilised in a glass vial with a rubber stopper and an aluminium flip-off crimp. Chemically it is a robust molecule: the lactam bridge, the D-amino acid, the norleucine in place of methionine and the capped termini were all chosen to resist degradation, and there is no disulphide to scramble and no lipid chain to aggregate. The one vulnerability is the tryptophan, which oxidises in the presence of light, peroxides and transition metals.

Sealed vial. Store at 2–8 °C for routine use and at −20 °C or below for storage beyond a few months. Protect from light; keep the vial in its carton or an amber secondary container. Avoid repeated freeze–thaw cycles. Allow a refrigerated vial to reach room temperature before opening so that moisture does not condense onto the cake.

Reconstitution. For in-vitro work the compound is reconstituted in sterile water, bacteriostatic water or a buffer appropriate to the assay. With the lysine side chain tied up in the lactam, the net positive charge at neutral pH comes from the arginine and histidine, and the molecule dissolves readily in water and in acidic to neutral buffers. Add the solvent down the side of the vial and swirl gently; the cake should clear within seconds. For receptor assays a concentrated stock in water or a small volume of DMSO is usually prepared and diluted into assay buffer; the reconstitution calculator gives the volume to add for a target concentration.

Reconstituted solution. Keep at 2–8 °C, protected from light. Aqueous solutions of MT-2 are more stable than those of most short linear peptides, but the tryptophan will still oxidise over weeks. The conservative practice is to aliquot into single-use volumes, freeze at −20 °C or below and use within a month. Discard any solution that develops colour; a yellow tint is a sign of tryptophan oxidation products.

Solubility and adsorption. MT-2 is freely soluble in water, acetate and phosphate buffers and DMSO at research concentrations. It is cationic and somewhat hydrophobic, and will adsorb to untreated glass and some plastics at very low concentrations; for dilute working solutions, low-binding tubes or a carrier protein such as 0.1% bovine serum albumin are standard. Where filtration is needed a 0.22 µm PVDF or PES membrane is appropriate; avoid nylon, which binds basic peptides.

What a sound certificate for MT-2 looks like

Every batch we release carries an independent certificate of analysis, and the figures from it are transcribed on the product page and in the certificate register. The Breindahl study is the clearest demonstration in the literature of why this matters for this compound in particular: products sold as Melanotan II on the open internet varied in content, contained synthesis-related impurities and, in some cases, contained a different peptide entirely [16]. For MT-2 a certificate should contain the following.

Purity by RP-HPLC. Reversed-phase HPLC on a C18 column with UV detection reports purity as the area of the main peak as a percentage of all integrated peaks. For MT-2 the wavelength matters: the tryptophan absorbs strongly at 280 nm as well as at the peptide-bond wavelengths of 214–220 nm, and a certificate reporting both is more informative, since a tryptophan-oxidised impurity changes its 280 nm profile. A good batch shows a single dominant peak with purity of 98% or above. The principal synthesis-related impurities in a cyclic lactam are the uncyclised linear precursor, 18 Da heavier, and racemisation products at the D-Phe position; both elute close to the main peak and are best seen on the chromatogram rather than in a bare number.

Identity by LC-MS. Electrospray mass spectrometry confirms that the main peak has the expected mass. For MT-2 the average molecular weight is 1024.18 Da and the monoisotopic mass approximately 1023.5 Da. A peptide of this size and charge appears predominantly as the doubly charged [M+2H]2+ ion at about 512.8 and the singly charged [M+H]+ at about 1024.5, and a certificate may report either or a deconvoluted mass, which should agree with theory to within about 0.5 Da. A mass 18 Da high indicates the uncyclised linear peptide; 1 Da high indicates the free acid (the bremelanotide-type C-terminus) in place of the amide, a distinct compound that should prompt a question about what has been supplied; 16 or 32 Da high indicates tryptophan oxidation.

Net peptide content. Lyophilised peptides contain bound water and counter-ions, and MT-2 with its basic residues carries a significant counter-ion fraction, acetate after an exchange step or trifluoroacetate straight from purification. Net peptide content, where reported, is the fraction of the powder that is actual peptide and is what should be used when calculating molar concentrations. A certificate should also state which counter-ion is present, since residual trifluoroacetate is itself active in some cell assays.

Endotoxin. Where the batch has been tested, a limulus amoebocyte lysate (LAL) result is reported in endotoxin units per milligram, which matters in cell-based assays using immune cells that themselves express MC1R and MC3R.

Our guide to reading a certificate of analysis goes through a complete report line by line.

Related compounds

PT-141, bremelanotide, is the free-acid metabolite of MT-2 identified by Palatin and carried through clinical development in its place [7]. It differs from MT-2 by a single substitution at the C-terminus, shares its non-selective melanocortin agonism, and is the only member of the series to have been licensed anywhere; it is the natural comparator in any assay in which MT-2 is the reference agonist. GHK-Cu, the copper-binding tripeptide, shares a class with MT-2 in our catalogue for reasons of dermatological research interest rather than pharmacology: GHK-Cu acts through copper delivery and gene expression, MT-2 through a defined receptor family. Afamelanotide (Melanotan I), the linear analogue from which MT-2 was derived [1, 3], is a licensed medicine and is not supplied by BuyUK Peptides.

Frequently asked questions

Is MT-2 the same thing as Melanotan I? No. Melanotan I (afamelanotide) is a linear 13-residue analogue of full-length α-MSH; MT-2 is a cyclic seven-residue analogue of its 4–10 core [1, 3]. The two have been confused in both the popular and the medical literature.

Is MT-2 the same thing as PT-141? No, although they are closely related. PT-141 (bremelanotide) is the C-terminal free acid of MT-2 and was identified as a metabolite of it [7]. LC-MS distinguishes them by a 1 Da mass difference.

Is it licensed anywhere? No. It has never received a marketing authorisation in any country, and clinical development was discontinued around 2000 in favour of bremelanotide [3, 7].

Why has the MHRA warned about it? Because it has been sold as an injectable tanning product, which is an unlicensed medicine under UK law, and because the case literature associates that use with naevus changes, melanoma, rhabdomyolysis, priapism and renal injury [8–15]. BuyUK Peptides supplies MT-2 for in-vitro research only.

Is it on the WADA list? Not by name, but it falls within the S0 category of non-approved substances, which is prohibited at all times.

How long does a sealed vial last? A cyclic, capped peptide of this kind is stable for years at −20 °C and for many months at 2–8 °C if protected from light. The batch certificate reports the test date; the storage guidance on this page applies from receipt.

References

1. Al-Obeidi F, Hadley ME, Pettitt BM, Hruby VJ. Design of a new class of superpotent cyclic α-melanotropins based on quenched dynamic simulations. Journal of the American Chemical Society. 1989;111(9):3413–3416. doi:10.1021/ja00191a044.
2. Al-Obeidi F, Castrucci AM, Hadley ME, Hruby VJ. Potent and prolonged-acting cyclic lactam analogues of α-melanotropin: design based on molecular dynamics. Journal of Medicinal Chemistry. 1989;32(12):2555–2561. doi:10.1021/jm00132a010.
3. Hadley ME, Dorr RT. Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Peptides. 2006;27(4):921–930. doi:10.1016/j.peptides.2005.01.029.
4. Dorr RT, Lines R, Levine N, et al. Evaluation of Melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sciences. 1996;58(20):1777–1784. doi:10.1016/0024-3205(96)00160-9.
5. Hruby VJ, Lu D, Sharma SD, et al. Cyclic lactam α-melanotropin analogues of Ac-Nle4-cyclo[Asp5,D-Phe7,Lys10]-α-melanocyte-stimulating hormone-(4-10)-NH2 with bulky aromatic amino acids at position 7 show high antagonist potency and selectivity at specific melanocortin receptors. Journal of Medicinal Chemistry. 1995;38(18):3454–3461. doi:10.1021/jm00018a005.
6. Wessells H, Gralnek D, Dorr R, Hruby VJ, Hadley ME, Levine N. Effect of an alpha-melanocyte stimulating hormone analog on penile erection and sexual desire in men with organic erectile dysfunction. Urology. 2000;56(4):641–646. doi:10.1016/S0090-4295(00)00680-4.
7. Molinoff PB, Shadiack AM, Earle D, Diamond LE, Quon CY. PT-141: a melanocortin agonist for the treatment of sexual dysfunction. Annals of the New York Academy of Sciences. 2003;994(1):96–102. doi:10.1111/j.1749-6632.2003.tb03167.x.
8. Evans-Brown M, Dawson RT, Chandler M, McVeigh J. Use of melanotan I and II in the general population. BMJ. 2009;338:b566. doi:10.1136/bmj.b566.
9. Cancer Research UK. Melanotan injections are illegal and possibly unsafe. Science blog, 28 January 2009, reporting the MHRA warning and enforcement letters. news.cancerresearchuk.org.
10. Habbema L, Halk AB, Neumann M, Bergman W. Risks of unregulated use of alpha-melanocyte-stimulating hormone analogues: a review. International Journal of Dermatology. 2017;56(10):975–980. doi:10.1111/ijd.13585.
11. Cardones AR, Grichnik JM. α-Melanocyte-stimulating hormone-induced eruptive nevi. Archives of Dermatology. 2009;145(4):441–444. doi:10.1001/archdermatol.2008.623.
12. Ong S, Bowling J. Melanotan-associated melanoma in situ. Australasian Journal of Dermatology. 2012;53(4):301–302. doi:10.1111/j.1440-0960.2012.00915.x.
13. Nelson ME, Bryant SM, Aks SE. Melanotan II injection resulting in systemic toxicity and rhabdomyolysis. Clinical Toxicology. 2012;50(10):1169–1173. doi:10.3109/15563650.2012.740637.
14. Dreyer BA, Amer T, Fraser M. Melanotan-induced priapism: a hard-earned tan. BMJ Case Reports. 2019;12(2):e227644. doi:10.1136/bcr-2018-227644.
15. Peters B, Hadimeri H, Wahlberg J, Afghahi H. Melanotan II: a possible cause of renal infarction: review of the literature and case report. CEN Case Reports. 2020;9(2):159–161. doi:10.1007/s13730-020-00447-z.
16. Breindahl T, Evans-Brown M, Hindersson P, et al. Identification and characterization by LC-UV-MS/MS of melanotan II skin-tanning products sold illegally on the Internet. Drug Testing and Analysis. 2015;7(2):164–172. doi:10.1002/dta.1655.

This monograph summarises the published literature for laboratory researchers. It is not medical advice, and nothing on this site is for human or veterinary use.