PET of CXCR4 Expression by a ⁶⁸Ga-Labeled Highly Specific Targeted Contrast Agent

Abstract

The overexpression of the chemokine receptor CXCR4 plays an important role in oncology, since together with its endogenous ligand, the stromal cell-derived factor (SDF1-a), CXCR4 is involved in tumor development, growth, and organ-specific metastasis. As part of our ongoing efforts to develop highly specific CXCR4-targeted imaging probes and with the aim to assess the suitability of this ligand for first proof-of-concept studies in humans, we further evaluated the new 68 Ga-labeled high-affinity cyclic CXCR4 ligand, 68 Ga-CPCR4-2 (cyclo(D- 68 Ga-DOTA]-Arg 3 -2-Nal 4 -Gly 5 )). Methods: Additional biodistribution and competitions studies in vivo, dynamic PET studies, and investigations on the metabolic stability and plasma protein binding were performed in nude mice bearing metastasizing OH1 human small cell lung cancer xenografts. CXCR4 expression on OH1 tumor sections was determined by immunohistochemical staining. Results: nat Ga-CPCR4-2 exhibits high CXCR4 affinity with a half maximum inhibitory concentration of 4.99 6 0.72 nM. 68 Ga-CPCR4-2 showed high in vivo stability and high and specific tumor accumulation, which was reduced by approximately 80% in competition studies with AMD3100. High CXCR4 expression in tumors was confirmed by immunohistochemical staining. 68 Ga-CPCR4-2 showed low uptake in nontumor tissue and particularly low kidney accumulation despite predominant renal excretion, leading to high-contrast delineation of tumors in small-animal PET studies. Conclusion: The small and optimized cyclic peptide CPCR4-2 labeled with 68 Ga is a suitable tracer for targeting and imaging of human CXCR4 receptor expression in vivo. The high affinity for CXCR4, its in vivo stability, and the excellent pharmacokinetics recommend the further evaluation of 68 Ga-CPCR4-2 in a proof-of-concept study in humans.

First Experience with Chemokine Receptor CXCR4–Targeted PET Imaging of Patients with Solid Cancers

“…Our results indicate that the detectability of solid cancers may generally be lower on 68 Ga-pentixafor PET than on 18 F-FDG PET. These preliminary findings indicate that, for use as a standard oncologic tool, CXCR4-targeted PET does not seem as suitable as 18 F-FDG PET. However, the potential of CXCR4-targeted PET might be found in certain specialized applications yet to be elucidated.…”

“…Details of the per-patient analysis are presented in Table 2. The Spearman test revealed a low correlation in SUV max between 18 F-FDG PET and 68 Ga-pentixafor PET (r 5 0.3; P 5 0.99). 1.…”

“…In addition, whole-body dosimetry studies on humans revealed excellent pharmacokinetics and thus low radiation burden to patients (20). Subsequent PET investigations on mice xenografted with human CXCR4-positive multiple myeloma cell lines and patients with advanced multiple myeloma provided high-contrast images with higher detection rates for multiple myeloma manifestations than can be achieved with standard 18 F FDG PET/CT scans (21).…”

“…To meet the clinical need for a highly specific and sensitive tool for in vivo CXCR4 assessment and quantification, 68 Ga-pentixafor (formerly known as 68 Ga-CPCR4.2), a CXCR4-targeted high-affinity nuclear probe, has been developed and evaluated in small cell lung cancer models for PET by Wester's group (17,18). Proof-of-concept investigations on lymphoma-xenografted animal models and the first investigations on patients with hematologic malignancies confirmed high tracer accumulation in tumors, low uptake in background, and concomitantly fast tracer clearance from nontargeted tissues (18,19). In addition, whole-body dosimetry studies on humans revealed excellent pharmacokinetics and thus low radiation burden to patients (20).…”

First-in-Human Experience of CXCR4-Directed Endoradiotherapy with 177Lu- and 90Y-Labeled Pentixather in Advanced-Stage Multiple Myeloma with Extensive Intra- and Extramedullary Disease

“…CXCR4 is overexpressed in multiple myeloma cells (9,10). Wester's group has successfully developed a radiolabeled CXCR4 ligand ( 68 Ga-pentixafor) for PET imaging (11,12). Proof of concept for visualization of CXCR4 expression has recently been demonstrated in patients with lymphoma (13) and multiple myeloma (14).…”