title: PET of CXCR4 expression by a (68)Ga-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-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 (68)Ga-labeled high-affinity cyclic CXCR4 ligand, (68)Ga-CPCR4-2 (cyclo(D-Tyr(1)-[NMe]-D-Orn(2)-[4-(aminomethyl) benzoic acid,(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 ± 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.
  
  
  CONCLUSIONS
  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.
authors: Pharmaceutical Radiochemistry, Technische Universität München, Garching, Germany.
authors: Eleni
authors: E
authors: Gourni
authors: Oliver
authors: O
authors: Demmer
authors: Margret
authors: M
authors: Schottelius
authors: Calogero
authors: C
authors: D'Alessandria
authors: Stefan
authors: S
authors: Schulz
authors: Ingrid
authors: I
authors: Dijkgraaf
authors: Udo
authors: U
authors: Schumacher
authors: Markus
authors: M
authors: Schwaiger
authors: Horst
authors: H
authors: Kessler
authors: Hans-Jürgen
authors: HJ
authors: Wester
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D003287:Contrast Media / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D005260:Female; D005629:Frozen Sections; D005710:Gallium Radioisotopes; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007553:Isotope Labeling; D019169:Jurkat Cells; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D021381:Protein Transport; D019718:Receptors, CXCR4 / Q000378:metabolism*; D055752:Small Cell Lung Carcinoma / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D013379:Substrate Specificity
chemical_list: D003287:Contrast Media; D005710:Gallium Radioisotopes; D010456:Peptides, Cyclic; D019718:Receptors, CXCR4