Abstract
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, [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.MethodsNOTA-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).ConclusionsDespite 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.
Highlights
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
This has led to the development of tools for the non-invasive in vivo quantification of Chemokine receptor 4 (CXCR4) expression in order to improve prognostication and personalized therapy [4]. [68Ga]pentixafor, formerly termed [68Ga]CPCR4.2 (Fig. 1), represents a milestone in the development of CXCR4-targeted positron emission tomography (PET) probes [5, 6], since its pharmacokinetic properties and favorable dosimetry [7] led to a fast transition into first clinical studies, including in vivo quantification of CXCR4 expression in various types of cancers [8,9,10,11,12,13] and after myocardial infarction
We recently reported the influence of different metalchelate conjugates of pentixafor on the CXCR4 affinity [21] and found that the NOTA conjugate NOTA-pentixafor (Fig. 1) displayed the highest CXCR4 affinity among various tracers
Summary
General procedures and syntheses of the peptides are described in a recently reported protocol [21]. While the tumor accumulation of [68Ga]pentixafor is higher than activity uptake in all other organs, leading to excellent tumor/background ratios (Table 2), uptake of [68Ga]NOTA-pentixafor in the Daudi xenografts is surprisingly low, albeit CXCR4 specific. This is illustrated by the competition experiment, where co-injection of 50 μg AMD3100 reduced tumor uptake by 70 %. As expected from the biodistribution data, [68Ga]NOTA-pentixafor uptake in the Daudi xenograft was CXCR4 specific (Fig. 2b), and despite low total activity accumulation, tumors were clearly delineated 1.5 h p.i. In contrast to [68Ga]pentixafor, which shows virtually no background accumulation except in kidneys [12], [68Ga]NOTA-pentixafor shows considerable activity accumulation in the gall bladder, intestines, and kidneys
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