RGD peptides

Arg-Gly-Asp peptides; cilengitide (EMD 121974, cyclo(-RGDfV(NMe)-)); F-18 galacto-RGD; F-18 fluciclatide (AH111585); F-18 alfatide; Ga-68 NOTA-PRGD2; Tc-99m maraciclatide (NC100692); Ga-68/F-18 "integrin PET"

Oncology & imaging

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Summary

Class: Synthetic cyclic pentapeptides containing the Arg-Gly-Asp (RGD) motif. Cilengitide is an unlabelled therapeutic cyclic peptide; the imaging agents are cyclic RGD peptides (often dimers) carrying a chelator or F-18 prosthetic group
Mechanism: RGD is the three-amino-acid sequence that extracellular-matrix proteins use to grip integrin receptors; cyclic RGD peptides bind integrin αvβ3 (and αvβ5) on tumour blood vessels and some tumour cells, either blocking them (cilengitide) or carrying an isotope to image them
Routes studied: Intravenous (imaging; cilengitide infusions). Cilengitide was also studied intratumourally in early work
Half-life: Cilengitide plasma half-life ~3–5 h †. Imaging tracers: isotope half-life (F-18 110 min, Ga-68 68 min, Tc-99m 6 h) with renal clearance of peptide within hours
Storage: Hospital radiopharmacy only for tracers; cilengitide is no longer in development
Regulatory status: None approved. Cilengitide development discontinued after Phase 3 (2014); RGD tracers investigational

Doses are as reported in studies or by the community — never recommendations.

1What it is

"RGD" is the three-letter code for arginine-glycine-aspartate, a short sequence discovered in the 1980s to be the part of fibronectin that cells grab onto. Integrins — the receptors that do the grabbing — are abundant on new blood vessels, and the αvβ3 integrin in particular is heavily expressed on tumour vasculature and on glioblastoma, melanoma and some other tumour cells. Two lines of work grew from this.

Cilengitide, a cyclic pentapeptide designed in the 1990s with a D-phenylalanine and N-methyl valine to lock the RGD loop in the right shape, was the first integrin inhibitor to reach Phase 3 as an anti-angiogenic cancer drug. The imaging line attached PET or SPECT isotopes to similar cyclic RGD peptides to picture non-invasively. Cilengitide failed its pivotal trial; the imaging tracers remain research tools.

2How it's thought to work

Cilengitide. competitively blocks αvβ3 and αvβ5 integrins, which in theory should stop endothelial cells from adhering and migrating, starving tumours of new blood supply and detaching integrin-dependent tumour cells. Later work complicated this: at low concentrations some RGD mimetics appear to paradoxically stimulate (Reynolds 2009, Nat Med), and integrin signalling is highly redundant.

RGD imaging. tracer uptake correlates with αvβ3 density measured by immunohistochemistry in several tumour types; uptake reflects both tumour-cell and vascular integrin, so it is a marker of "angiogenic activity" rather than of tumour burden. Dimeric and multimeric RGD constructs bind more tightly than monomers.

The arginine-glycine-aspartate motif, the sequence integrins read when a cell grips the matrix around it. The same three residues appear in drugs that stop that grip and in tracers that use it to carry a label to the cells displaying the receptor.Schematic — not to scale

3What the research shows

Graded A (negative)

Cilengitide in newly diagnosed glioblastoma

CENTRIC (n=545) randomised patients with MGMT-promoter-methylated glioblastoma to standard temozolomide chemoradiotherapy with or without cilengitide 2,000 mg twice weekly; median overall survival was 26.3 vs 26.3 months (HR 1.02). The drug did not help (Stupp 2014, Lancet Oncol). The companion CORE Phase 2 in unmethylated tumours showed at most a marginal signal (Nabors 2015, Neuro Oncol). Development stopped. [2][3]

Graded A/B (negative or null)

Cilengitide in other cancers

Phase 2 trials in recurrent glioblastoma (Reardon 2008, J Clin Oncol — modest response), non-small-cell lung cancer (CERTO) and head and neck cancer (ADVANTAGE) showed acceptable safety but no convincing efficacy. [4]

RGD PET imaging of αvβ3 expression

F-18 galacto-RGD was the first clinical tracer, showing uptake that correlated with αvβ3 immunohistochemistry in melanoma, sarcoma and head and neck cancer (Haubner 2005, PLoS Med; Beer 2006, J Nucl Med). F-18 fluciclatide and F-18 alfatide reached multicentre Phase 1–2 studies in lung and breast cancer, with sensitivity broadly comparable to FDG but lower uptake intensity (Kenny 2008, J Nucl Med; Wan 2013, J Nucl Med). None progressed to registration. [6][7][8][9]

Graded B (small)

RGD imaging for anti-angiogenic therapy response

Pilot studies suggested early changes in RGD uptake after bevacizumab or other anti-angiogenics; underpowered and inconsistent.

Graded B/C

RGD imaging beyond cancer (myocardial infarction, atherosclerosis, endometriosis)

Small human studies with Tc-99m maraciclatide and F-18 RGD tracers show uptake in healing myocardium and in endometriotic lesions; a UK study of maraciclatide for endometriosis detection was reported in 2023–2024 †.

Graded C/—

RGD-based radioligand therapy

Lu-177 or Y-90 RGD multimers have been tested in animals; isolated human reports only.

4Reported side effects and interactions

Literature-reported

Literature (cilengitide). generally well tolerated; the most frequent attributed events were nausea, fatigue, lymphopenia and modest increases in thromboembolic and haemorrhagic events in some trials (a theoretical concern for any anti-angiogenic). No dose-limiting toxicity was reached in Phase 1 up to 2,400 mg/m².

Literature (RGD tracers). no significant adverse events reported in Phase 1–2 imaging studies; radiation dose similar to other F-18 and Ga-68 peptide tracers.

Community-reported

essentially none documented. Occasional online discussion of RGD peptides in a "research chemical" context refers to the unlabelled peptide and has no human data behind it.

Theoretical. the Reynolds 2009 finding that low-dose RGD mimetics can promote is the main cautionary note for any RGD-based therapy.

Interactions. none established.

Markers researchers commonly monitor

No compound-specific markers exist for diagnostic use. In cilengitide trials and conceptually for any anti-angiogenic:

Marker	Why it's watched
CBC	lymphopenia was observed with cilengitide.
Coagulation and clinical surveillance for bleeding or clotting	class-level anti-angiogenic concern.
Blood pressure	raised by many anti-angiogenics; not prominent with cilengitide but tracked.
MRI-based response (RANO criteria) in glioma	the outcome measure in the pivotal trials.
αvβ3 immunohistochemistry on tumour tissue	the reference standard against which RGD PET uptake is validated.

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

Not applicable to individuals. Radiolabelled RGD tracers are prepared in research radiopharmacies; cilengitide was a hospital IV infusion that is no longer manufactured for clinical use. No calculator link is provided for this compound.

6Commonly studied alongside

Temozolomide and radiotherapy (cilengitide trials); bevacizumab (as the anti-angiogenic whose effect RGD imaging tried to monitor); FAPI (#206) and PSMA ligands (#203) as other stroma- or vasculature-related radiotracers.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	Cilengitide never approved (orphan designation for glioblastoma lapsed). RGD imaging agents investigational only
European Union	Cilengitide never authorised. RGD tracers investigational
United Kingdom	Not licensed; Tc-99m maraciclatide studied in NHS research settings †
Australia	Not approved
South Africa	Not registered
Sport (WADA)	Cilengitide and unlabelled RGD peptides would fall under S0 (non-approved substances) if used by athletes; no cases known †

8Open questions

Why cilengitide failed despite target engagement: dose/schedule (its short and twice-weekly dosing were criticised), the paradoxical effect, or integrin redundancy.
Whether RGD PET can select patients for integrin-directed or anti-angiogenic therapy in a way that changes outcomes.
Whether RGD-targeted radionuclide therapy is viable given low tumour-cell expression in most carcinomas.

9References

1Dechantsreiter MA et al. (1999). N-methylated cyclic RGD peptides as highly active and selective αvβ3 integrin antagonists. J Med Chem. PubMed · DOI
2Stupp R et al. (2014). Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. PubMed
3Nabors LB et al. (2015). Two cilengitide regimens in combination with standard treatment for patients with newly diagnosed glioblastoma and unmethylated MGMT gene promoter: results of the open-label, controlled, randomized phase II CORE study. Neuro Oncol. PubMed
4Reardon DA et al. (2008). Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol. PubMed · DOI
5Reynolds AR et al. (2009). Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat Med. PubMed · DOI
6Haubner R et al. (2005). Noninvasive visualization of the activated αvβ3 integrin in cancer patients by positron emission tomography and [18F]Galacto-RGD. PLoS Med. PubMed · DOI
7Beer AJ et al. (2006). Positron emission tomography using [18F]Galacto-RGD identifies the level of integrin αvβ3 expression in man. Clin Cancer Res. PubMed · DOI
8Kenny LM et al. (2008). Phase I trial of the positron-emitting Arg-Gly-Asp (RGD) peptide radioligand 18F-AH111585 in breast cancer patients. J Nucl Med. PubMed · DOI
9Wan W et al. (2013). First experience of 18F-alfatide in lung cancer patients using a new lyophilized kit for rapid radiofluorination. J Nucl Med. PubMed · DOI

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

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11Page history

31 Oct 2026Profile published — awaiting medical review

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