Abstract
In vivo quantification of CXCR4 expression using [68Ga]pentixafor for positron emission tomography (PET) imaging has gained significant clinical interest as CXCR4 plays a fundamental role in oncology and possesses potential prognostic value when overexpressed. To combine the excellent CXCR4-targeting properties of pentixafor-based tracers with the favorable radionuclide properties of 18F for high-resolution PET imaging, we developed an Al18F-labeled 1,4,7-triazacyclononane-triacetic acid (NOTA) analog of pentixather. Al18F-labeling of NOTA-pentixather was performed in aqueous dimethyl sulfoxide (DMSO) at pH = 4 (105°C, 15 minutes). CXCR4 affinities were determined in competitive binding assays, and both biodistribution and small-animal PET studies were performed in Daudi lymphoma-bearing mice. Under non-optimized conditions, [18F]AlF-NOTA-pentixather was obtained in radiochemical yields of 45.5% ± 13.3% and specific activities of up to 24.8 GBq/μmol. Compared with [natGa]pentixafor, [natF]AlF-NOTA-pentixather showed 1.4-fold higher CXCR4 affinity. [18F]AlF-NOTA-pentixather displayed high and CXCR4-specific in vivo uptake in Daudi xenografts (13.9% ± 0.8% injected dose per gram [ID/g] at 1 hour post injection [p.i.]). Because of its enhanced lipophilicity (logP = −1.4), [18F]AlF-NOTA-pentixather showed increased accumulation in the gall bladder and intestines. However, tumor/background ratios of 7.0 ± 1.2, 2.0 ± 0.3, 2.2 ± 0.4, 16.5 ± 6.5, and 29.2 ± 4 for blood, liver, small intestine, gut, and muscle, respectively, allowed for high-contrast visualization of Daudi tumors using PET (1 hour p.i.). The relatively straightforward radiosynthesis and efficient CXCR4 targeting of [18F]AlF-NOTA-pentixather demonstrate the successful implementation of 18F-complexation chemistry and pentixather-based CXCR4 targeting. Upon pharmacokinetic optimization, this class of tracers holds great promise for future application in humans.
Highlights
Overexpression of the chemokine receptor CXCR4 has been linked to cancer development and progression, metastasis and poor prognosis, as well as other pathological conditions, for example, HIV, cardiovascular diseases, and rheumatoid arthritis [1,2,3]
When AlnatF labeling was carried out in the solvent systems containing either 70% dimethyl sulfoxide (DMSO) or 70% ETOH (v/v), [natF]AlFNOTA- and [natF]AlF-NODA-NCS-pentixather were obtained in yields of 59% and 90%, respectively
We could show that small structural modifications in the peptide backbone, leading to pentixather [38, 41], provide a molecular scaffold with much higher flexibility toward structural modification and a greater bandwidth of possible radiolabeling strategies
Summary
Overexpression of the chemokine receptor CXCR4 has been linked to cancer development and progression, metastasis and poor prognosis, as well as other pathological conditions, for example, HIV, cardiovascular diseases, and rheumatoid arthritis [1,2,3]. The development of novel synthetic CXCR4 antagonists was primarily triggered by the discovery of CXCR4 as a coreceptor for HIV-1 entry, leading to the development of potent synthetic CXCL12-analogs such as the tetradecapeptide T140 and the cyclic pentapeptide FC131, as well as the nonpeptidic bicyclam analog AMD3100 (plerixafor), for anti-HIV therapy [4,5,6] Based on these lead structures, a variety of CXCR4-targeted agents for molecular imaging applications have been developed in recent years, allowing the sensitive in vivo detection and quantification of CXCR4 expression, and providing increasing insight into the role of CXCR4 in physiology and pathology.
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