PET of CXCR4 Expression by a 68Ga-Labeled Highly Specific Targeted Contrast Agent
Open Access
- 1 November 2011
- journal article
- Published by Society of Nuclear Medicine in Journal of Nuclear Medicine
- Vol. 52 (11), 1803-1810
- https://doi.org/10.2967/jnumed.111.098798
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-α), 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 68Ga-labeled high-affinity cyclic CXCR4 ligand, 68Ga-CPCR4-2 (cyclo(D-Tyr1-[NMe]-D-Orn2-[4-(aminomethyl) benzoic acid,68Ga-DOTA]-Arg3-2-Nal4-Gly5)). 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: natGa-CPCR4-2 exhibits high CXCR4 affinity with a half maximum inhibitory concentration of 4.99 ± 0.72 nM. 68Ga-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. 68Ga-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 68Ga 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 68Ga-CPCR4-2 in a proof-of-concept study in humans.Keywords
This publication has 33 references indexed in Scilit:
- Dipyrimidine Amines: A Novel Class of Chemokine Receptor Type 4 Antagonists with High SpecificityJournal of Medicinal Chemistry, 2010
- Discovery of Small Molecule CXCR4 AntagonistsJournal of Medicinal Chemistry, 2007
- Chemokines and cancerInternational Journal of Cancer, 2006
- CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironmentBlood, 2006
- Possible role of stromal-cell-derived factor-1/CXCR4 signaling on lymph node metastasis of oral squamous cell carcinomaExperimental Cell Research, 2003
- The Stromal Derived Factor–1/CXCL12–CXC Chemokine Receptor 4 Biological Axis in Non–Small Cell Lung Cancer MetastasesAmerican Journal of Respiratory and Critical Care Medicine, 2003
- Guidance of Primordial Germ Cell Migration by the Chemokine SDF-1Cell, 2002
- Chemokines in the Inflammatory Bowel DiseasesJournal of Clinical Immunology, 1999
- A Low-Molecular-Weight Inhibitor against the Chemokine Receptor CXCR4: A Strong Anti-HIV Peptide T140Biochemical and Biophysical Research Communications, 1998
- Introduction: HIV co-receptors solve old questions and raise many new onesSeminars in Immunology, 1998