Preclinical evaluation of 68GaNOTA-pentixafor for PET imaging of CXCR4 expression in vivo — a comparison to 68GapentixaforReport as inadecuate

Preclinical evaluation of 68GaNOTA-pentixafor for PET imaging of CXCR4 expression in vivo — a comparison to 68Gapentixafor - Download this document for free, or read online. Document in PDF available to download.

EJNMMI Research

, 6:70

First Online: 21 September 2016Received: 18 July 2016Accepted: 17 September 2016DOI: 10.1186-s13550-016-0227-2

Cite this article as: Poschenrieder, A., Schottelius, M., Schwaiger, M. et al. EJNMMI Res 2016 6: 70. doi:10.1186-s13550-016-0227-2


BackgroundDue to its overexpression in a variety of tumor types, the chemokine receptor 4 CXCR4 represents a highly relevant diagnostic and therapeutic target in nuclear oncology. Recently, Gapentixafor has emerged as an excellent imaging agent for positron emission tomography PET of CXCR4 expression in vivo. In this study, the corresponding Ga-1,4,7-triazacyclononane-triacetic acid NOTA analog was preclinically evaluated and compared to the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid DOTA parent compound Gapentixafor.

MethodsNOTA-pentixafor was synthesized by combining solid and solution-phase peptide synthesis. The CXCR4 receptor affinities of Gapentixafor and GaNOTA-pentixafor were determined in competitive binding assays using the leukemic CXCR4-expressing Jurkat T-cell line and IFC131 as the radioligand. Internalization and cell efflux assays were performed using CXCR4-transfected Chem-1 cells. Small-animal PET and biodistribution studies were carried out using Daudi-tumor bearing SCID mice.

ResultsGaNOTA-pentixafor showed a 1.4-fold improved affinity towards CXCR4 IC50. However, internalization efficiency into CXCR4-Chem-1 cells was substantially decreased compared to Gapentixafor. Accordingly, small-animal PET imaging and biodistribution studies revealed a 9.5-fold decreased uptake of GaNOTA-pentixafor in Daudi lymphoma xenografts 1.7 ± 0.4 % vs 16.2 ± 3.8 % ID-g at 90 min p.i. and higher levels of non-specific accumulation, primarily in the excretory organs such as the liver, intestines, and kidneys 2.3 ± 0.9 % vs 2.0 ± 0.3 % ID-g, 1.9 ± 0.8 % vs 0.7 ± 0.2 % ID-g, and 2.7 ± 1.1 % vs 1.7 ± 0.9 % ID-g, respectively.

ConclusionsDespite enhanced CXCR4-affinity in vitro, the GaNOTA-analog of pentixafor showed reduced CXCR4 targeting efficiency in vivo. In combination with enhanced background accumulation, this resulted in significantly inferior PET imaging contrast, and thus, GaNOTA-pentixafor offers no advantages over Gapentixafor.

KeywordsGPCR CXCR4 Gapentixafor Pentapeptide NOTA PET Radiopharmaceutical Tracer Cancer AbbreviationsASSpecific activity

CXCR4Chemokine receptor 4

DOTA1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

HER2Human epidermal growth factor receptor type 2

IC50Half maximal inhibitory concentration

NOTA1,4,7-triazacyclononane-triacetic acid

p.i.Post injection

PETPositron emission tomography

SDF-1Stromal cell derived factor-1

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Author: Andreas Poschenrieder - Margret Schottelius - Markus Schwaiger - Hans-Jürgen Wester


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