RPB

Pentixafor and pentixather

Pentixafor: CPCR4.2, Ga-68 pentixafor, [68Ga]boclatixafortide (INN), Ga-68 CPCR4-2. Pentixather: Lu-177 pentixather, Y-90 pentixather, iodinated pentixafor derivative for therapy

Oncology & imaging
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1What it is

CXCR4 is a receptor that normally guides white blood cells and stem cells toward tissues producing the chemokine CXCL12, including the bone marrow. Many cancers hijack it to home to the marrow and other protective niches, and high CXCR4 expression generally means worse prognosis. The approved drug plerixafor blocks CXCR4 to mobilise stem cells for collection, but it is a small molecule unsuited to imaging. German chemists in Munich developed a cyclic pentapeptide based on earlier CXCR4 antagonists (the FC131 family) and attached DOTA so that Ga-68 could be added without losing affinity; the result, pentixafor, entered human use around 2014. Because simply swapping Ga-68 for Lu-177 destroyed binding, a modified version — pentixather — was made for therapy. The imaging agent has since been studied in myeloma, lymphoma, leukaemia, solid tumours, primary aldosteronism and atherosclerosis and has progressed into sponsored Phase 3 imaging trials.

2How it's thought to work

Imaging. pentixafor binds CXCR4 with nanomolar affinity (for the human receptor; it binds mouse CXCR4 poorly, which complicates preclinical models). Tumour-to-background ratios are high because normal tissues other than spleen, bone marrow and kidneys express little CXCR4 at the cell surface.
Therapy. pentixather delivers beta radiation to CXCR4-positive cells — which include the malignant cells but also normal haematopoietic stem cells. The therapy is therefore by design myeloablative: it is given as part of a conditioning regimen before autologous or allogeneic stem-cell transplantation, not as a stand-alone treatment.
Endocrine use. aldosterone-producing adenomas express CXCR4 together with the aldosterone synthase enzyme, so pentixafor PET can lateralise primary aldosteronism without invasive adrenal vein sampling.
Vascular use. CXCR4 on inflammatory cells and progenitors in plaques and infarcted myocardium gives a signal for inflammation imaging.
A cyclic peptide ligand of the chemokine receptor CXCR4, labelled with gallium-68 for imaging or lutetium-177 for therapy. Targets the receptor rather than a tissue type.Schematic — not to scale

3What the research shows

Multiple myeloma imaging

First-in-human studies in 14 patients showed uptake in most with active disease and higher contrast than FDG in some (Philipp-Abbrederis 2015, EMBO Mol Med). Later series found pentixafor PET positive in roughly 60–70% of myeloma patients, complementary to FDG rather than superior, with uptake carrying prognostic weight (Lapa 2017, Theranostics; Pan 2020). [3][5]

Lymphoma, including marginal zone lymphoma and CNS lymphoma

Prospective studies report very high sensitivity for marginal zone lymphoma (a disease often FDG-negative) and for primary CNS lymphoma with low brain background (Duell 2021, J Nucl Med; Herhaus 2021 and others). This is the basis of the EU orphan designation and Phase 3 programme †. [6]

Primary aldosteronism

Prospective studies in Chinese and European cohorts report sensitivity around 85–90% for lateralising aldosterone-producing adenomas compared with adrenal vein sampling and surgical outcome (Ding 2020, Eur J Nucl Med Mol Imaging; Hu 2023, JAMA Netw Open prospective study) †. [8]

Solid tumours

Uptake is lower and more variable in solid tumours (small-cell lung cancer, adrenocortical carcinoma and some others show the highest uptake); not a general oncology tracer.
Graded B/C

Cardiovascular inflammation

Pilot human studies show uptake in atherosclerotic plaque and in myocardium after infarction, correlating with inflammatory cell infiltration (Thackeray 2015, JACC Cardiovasc Imaging). [7]
Graded B (small series)

Pentixather radioligand therapy

In heavily pretreated myeloma, acute leukaemia and T-cell lymphoma, Lu-177 or Y-90 pentixather given as part of transplant conditioning produced marrow ablation and some responses, with early-phase safety data in a few dozen patients overall (Herrmann 2016, J Nucl Med; Lapa 2017, J Nucl Med; Maurer 2019 and later reports). No randomised data; a Phase 1/2 programme is under way †. [4][5]

4Reported side effects and interactions

Literature-reported

Literature (pentixafor imaging). no significant adverse reactions reported across published studies; the radiation dose is similar to other Ga-68 peptide scans (~2–3 mSv). Diagnostic pitfalls include physiological uptake in spleen, marrow and kidneys and uptake in inflammation.

Literature (pentixather therapy). profound, intended myelosuppression requiring stem-cell rescue; infections and transfusion dependence during aplasia; kidney dose is significant and amino-acid protection is used; hepatic and gastrointestinal toxicity reported in combination with high-dose chemotherapy; treatment-related mortality has occurred in these very sick cohorts. Long-term risks (secondary malignancy, renal impairment) are unknown given small numbers and short survival of the populations studied.

Community-reported

Community use. essentially none documented.

Theoretical. CXCR4 on normal stem cells means any therapeutic use outside a transplant setting would be unsafe.

Interactions. plerixafor or other CXCR4 antagonists would block binding; corticosteroids have been reported to increase CXCR4 expression in some cells, potentially altering uptake; G-CSF mobilisation changes marrow signal.

Markers researchers commonly monitor

No markers apply to a diagnostic scan beyond disease-specific ones. In pentixather therapy protocols:

MarkerWhy it's watched
CBC with daily monitoring during aplasiamarrow ablation is the intended effect; recovery depends on the stem-cell graft.
Creatinine/eGFR and urinalysiskidneys receive a high dose; amino-acid co-infusion is used.
Liver enzymes and bilirubinhepatotoxicity reported in combination regimens.
Dosimetry imaging after a tracer dose of Lu-177 pentixatherused to plan the therapeutic activity and confirm marrow and tumour dose.
Disease markers (serum free light chains, M-protein, blast counts, PET)response assessment.
Aldosterone-to-renin ratio and adrenal vein sampling resultsin the primary aldosteronism imaging studies, as reference standards.

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

5Reconstitution and handling

Not applicable to individuals. Ga-68 pentixafor is prepared from a kit or precursor with generator eluate in hospital radiopharmacies under trial protocols; pentixather is labelled with Lu-177 or Y-90 at specialist centres. No calculator link is provided for this compound.

6Commonly studied alongside

FDG PET (the standard comparator in haematological malignancy); plerixafor (the approved CXCR4 antagonist, mechanistically related but not imaged); DOTATATE (#201) and PSMA ligands (#203) as the theranostic models; high-dose melphalan and allogeneic transplant conditioning regimens in pentixather studies.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

RegionStatus (checked —)
United StatesNot FDA-approved; investigational (IND studies in myeloma and other indications) †
European UnionNot authorised; Phase 3 imaging trials ongoing; PRIME eligibility and orphan designation for marginal zone lymphoma reported †; compassionate use at German academic centres
United KingdomNot licensed; research use only
AustraliaNot approved; research use †
South AfricaNot registered
Sport (WADA)Not listed

8Open questions

  • Will Ga-68 pentixafor reach approval, and for which indication first — marginal zone lymphoma, CNS lymphoma or primary aldosteronism?
  • Whether pentixather conditioning improves transplant outcomes compared with chemotherapy-based conditioning; randomised evidence is absent.
  • The prognostic and treatment-selection value of CXCR4 PET in myeloma given its complementarity with FDG.
  • Whether an F-18 or long-shelf-life kit version is needed for wider distribution.

9References

  1. 1Gourni E et al. (2011). PET of CXCR4 expression by a 68Ga-labeled highly specific targeted contrast agent. J Nucl Med. PubMed · DOI
  2. 2Wester HJ et al. (2015). Disclosing the CXCR4 expression in lymphoproliferative diseases by targeted molecular imaging. Theranostics. PubMed · DOI
  3. 3Philipp-Abbrederis K et al. (2015). In vivo molecular imaging of chemokine receptor CXCR4 expression in patients with advanced multiple myeloma. EMBO Mol Med. PubMed · DOI
  4. 4Herrmann K et al. (2016). First-in-human experience of CXCR4-directed endoradiotherapy with 177Lu- and 90Y-labeled pentixather in advanced-stage multiple myeloma with extensive intra- and extramedullary disease. J Nucl Med. PubMed · DOI
  5. 5Lapa C et al. (2017). CXCR4-directed endoradiotherapy induces high response rates in extramedullary relapsed multiple myeloma. Theranostics. PubMed · DOI
  6. 6Duell J et al. (2021). Improved primary staging of marginal-zone lymphoma by addition of CXCR4-directed PET/CT. J Nucl Med. PubMed · DOI
  7. 7Thackeray JT et al. (2015). Molecular imaging of the chemokine receptor CXCR4 after acute myocardial infarction. JACC Cardiovasc Imaging. PubMed · DOI
  8. 8Ding J et al. (2020). 68Ga-pentixafor PET/CT for the lateralization of primary aldosteronism. Eur J Nucl Med Mol Imaging. PubMed
  9. 9Buck AK et al. (2017). Chemokine receptor-directed imaging and therapy. Methods. 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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