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EJNMMI Research

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Open Access 01-12-2016 | Short Communication

Preclinical evaluation of [⁶⁸Ga]NOTA-pentixafor for PET imaging of CXCR4 expression in vivo — a comparison to [⁶⁸Ga]pentixafor

Authors: Andreas Poschenrieder, Margret Schottelius, Markus Schwaiger, Hans-Jürgen Wester

Published in: EJNMMI Research | Issue 1/2016

Abstract

Background

Due 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, [⁶⁸Ga]pentixafor has emerged as an excellent imaging agent for positron emission tomography (PET) of CXCR4 expression in vivo. In this study, the corresponding [⁶⁸Ga]-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 [⁶⁸Ga]pentixafor.

Methods

NOTA-pentixafor was synthesized by combining solid and solution-phase peptide synthesis. The CXCR4 receptor affinities of [⁶⁸Ga]pentixafor and [⁶⁸Ga]NOTA-pentixafor were determined in competitive binding assays using the leukemic CXCR4-expressing Jurkat T-cell line and [¹²⁵I]FC131 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.

Results

[⁶⁸Ga]NOTA-pentixafor showed a 1.4-fold improved affinity towards CXCR4 (IC₅₀). However, internalization efficiency into CXCR4⁺-Chem-1 cells was substantially decreased compared to [⁶⁸Ga]pentixafor. Accordingly, small-animal PET imaging and biodistribution studies revealed a 9.5-fold decreased uptake of [⁶⁸Ga]NOTA-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).

Conclusions

Despite enhanced CXCR4-affinity in vitro, the [⁶⁸Ga]NOTA-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, [⁶⁸Ga]NOTA-pentixafor offers no advantages over [⁶⁸Ga]pentixafor.

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Title: Preclinical evaluation of [68Ga]NOTA-pentixafor for PET imaging of CXCR4 expression in vivo — a comparison to [68Ga]pentixafor
Authors: Andreas Poschenrieder
Margret Schottelius
Markus Schwaiger
Hans-Jürgen Wester
Publication date: 01-12-2016
Publisher: Springer Berlin Heidelberg
Published in: EJNMMI Research / Issue 1/2016
Electronic ISSN: 2191-219X
DOI: https://doi.org/10.1186/s13550-016-0227-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Preclinical evaluation of [⁶⁸Ga]NOTA-pentixafor for PET imaging of CXCR4 expression in vivo — a comparison to [⁶⁸Ga]pentixafor

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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