Theranostics 2017; 7(9):2350-2362. doi:10.7150/thno.19119

Research Paper

[177Lu]pentixather: Comprehensive Preclinical Characterization of a First CXCR4-directed Endoradiotherapeutic Agent

Margret Schottelius1✉, Theresa Osl1, Andreas Poschenrieder1, Frauke Hoffmann1, Seval Beykan4, Heribert Hänscheid4, Andreas Schirbel4, Andreas K. Buck4, Saskia Kropf5, Markus Schwaiger3, 6, Ulrich Keller2, 6, Michael Lassmann4, Hans-Jürgen Wester1

1. Chair for Pharmaceutical Radiochemistry, Technische Universität München, Walther-Meissner-Strasse 3, 85748 Garching, Germany;
2. III. Medical Department, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675 Munich, Germany;
3. Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675 Munich, Germany;
4. Department of Nuclear Medicine, Universität Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, Germany;
5. Scintomics GmbH, Lindach 4, 82256 Fürstenfeldbruck, Germany;
6. Deutsches Konsortium für translationale Krebsforschung (DKTK) and Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license ( See for full terms and conditions.
Schottelius M, Osl T, Poschenrieder A, Hoffmann F, Beykan S, Hänscheid H, Schirbel A, Buck AK, Kropf S, Schwaiger M, Keller U, Lassmann M, Wester HJ. [177Lu]pentixather: Comprehensive Preclinical Characterization of a First CXCR4-directed Endoradiotherapeutic Agent. Theranostics 2017; 7(9):2350-2362. doi:10.7150/thno.19119. Available from

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Purpose: Based on the clinical relevance of the chemokine receptor 4 (CXCR4) as a molecular target in cancer and on the success of [68Ga]pentixafor as an imaging probe for high-contrast visualization of CXCR4-expression, the spectrum of clinical CXCR4-targeting was expanded towards peptide receptor radionuclide therapy (PRRT) by the development of [177Lu]pentixather.

Experimental design: CXCR4 affinity, binding specificity, hCXCR4 selectivity and internalization efficiency of [177Lu]pentixather were evaluated using different human and murine cancer cell lines. Biodistribution studies (1, 6, 48, 96h and 7d p.i.) and in vivo metabolite analyses were performed using Daudi-lymphoma bearing SCID mice. Extrapolated organ doses were cross-validated with human dosimetry (pre-therapeutic and during [177Lu]pentixather PRRT) in a patient with multiple myeloma (MM).

Results: [177Lu]pentixather binds with high affinity, specificity and selectivity to hCXCR4 and shows excellent in vivo stability. Consequently, and supported by >96% plasma protein binding and a logP=-1.76, delaying whole-body clearance of [177Lu]pentixather, tumor accumulation was high and persistent, both in the Daudi model and the MM patient. Tumor/background ratios (7d p.i.) in mice were 499±202, 33±7, 4.0±0.8 and 116±22 for blood, intestine, kidney and muscle, respectively. In the patient, high tumor/kidney and tumor/liver dose ratios of 3.1 and 6.4 were observed during [177Lu]pentixather PRRT (7.8 GBq), with the kidneys being the dose-limiting organs.

Conclusions: [177Lu]pentixather shows excellent in vivo CXCR4-targeting characteristics and a suitable pharmacokinetic profile, leading to high tumor uptake and retention and thus high radiation doses to tumor tissue during PRRT, suggesting high clinical potential of this [68Ga]pentixafor/[177Lu]pentixather based CXCR4-targeted theranostic concept.

Keywords: CXCR4, pentixafor, pentixather, PRRT, endoradiotherapy.