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Relationship Between Neutrophil-Binding Affinity and Suitability for Infection Imaging: Comparison of ^99mTc-Labeled NAP-2 (CXCL-7) and 3 C-Terminally Truncated Isoforms

¹ Department of Nuclear Medicine, University Medical Center Nijmegen, Nijmegen, The Netherlands
² Department of Immunology and Cell Biology, Forschungszentrum Borstel, Borstel, Germany
³ Department of Medical Microbiology, Academic Medical Center, Amsterdam, The Netherlands

The CXC chemokines are a family of closely related chemoattractant cytokines that bind to, attract, and activate neutrophils to variable degrees. In this study, the relationship between neutrophil-binding affinity and suitability for infection imaging was investigated in a selected group of CXC chemokines. Neutrophil–activating peptide-2 (NAP-2, 70 residues; also called CXCL7) binds with high affinity to the CXCR2 receptor on neutrophils. Recently, C-terminally truncated NAP-2-variants have been described that have enhanced neutrophil-binding affinity and neutrophil-stimulating capacity. Here, NAP-2 and its C-terminal shortened variants NAP-2(1–68), NAP-2(1–66), and NAP-2(1–63) were labeled with ^99mTc via the hydrazinonicotinamide (HYNIC) chelator and their potential for imaging of infection was investigated in a rabbit model of infection. The CXC chemokine interleukin-8 (IL-8) was used for comparison. In addition, a series of ^99mTc-labeled CXC chemokines were screened for their potential to image infection, including CTAP-III, GCP-2, ENA-78, PF-4, and IP-10. Methods: The receptor-binding affinity of HYNIC-conjugated NAP-2 and its analogs was compared in competitive binding assays on Jurkat cells transfected with the CXCR2 receptor gene. Biodistribution of labeled NAP-2 (analogs) and other CXC chemokines in rabbits with intramuscular Escherichia coli infections was determined both by -camera imaging and by counting dissected tissues at 6 h after injection. Results: The CXCR2-binding affinity of the HYNIC-conjugated NAP-2 analogs relative to NAP-2 was as follows: NAP-2(1–68), 2.5-fold; NAP-2(1–66), 10-fold; and NAP-2(1–63), 3-fold. In the rabbit model, uptake in the abscess (in percentage injected dose per gram ± SEM) was 0.084 ± 0.015 for NAP-2, 0.098 ± 0.010 for NAP-2(1–68), 0.189 ± 0.044 for NAP-2(1–66), and 0.114 ± 0.017 for NAP-2(1–63) at 6 h after injection. In comparison, higher uptake in the abscess was found for labeled IL-8, a modest uptake was found for GCP-2 and ENA-78, and a low uptake was found for CTAP-III, PF-4, and IP-10. Conclusion: This study showed a clear relationship between affinity to receptors on neutrophils and suitability for infection imaging. Of the NAP-2 variants, NAP-2(1–66) combined highest affinity to CXCR2 with the best characteristics for imaging. IL-8 binds to both CXCR1 and CXCR2 with high affinity and showed a superior imaging quality. The other CXC chemokines tested bind to neutrophils with lower affinity and were shown to be less suitable for infection imaging in this study.

Key Words: infection imaging • ^99mTc • NAP-2 analogs

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JNM 2004 45: 13A-14A. [Full Text]