[PubMed]

Chemokine receptors are G-protein–coupled receptors that direct cell movement (when activated by a ligand) toward higher concentrations of chemokines. Chemokine receptor 4 (CXCR4) and its ligand, stromal cell–derived factor-1 (SDF-1 or CXCL12), are known to play a major role in the migration of progenitor cells during embryonic development of the central nervous, cardiovascular, and hematopoietic systems (1, 2). In addition, this CXCR4/SDF-1 receptor system has a function in the development, progression, and spread of various cancers (3), and the CXCR4 acts as a co-receptor for human immunodeficiency virus (HIV) on CD4⁺ T cells (4). It has also been suggested that CXCR4/SDF-1 interaction participates in the pathogenesis of neurodegenerative and inflammatory conditions (5). CXCR4 is expressed by many different types of cancers, and overexpression of CXCR4 in cancers indicates poor prognosis with aggressive and metastatic tumors and resistance to chemotherapy (6).

CXCR4 is considered to play an important role in HIV infections and cancers (4). It is critical to perform imaging studies to measure CXCR4 levels under in vivo conditions for various pathological and physiological conditions (7). ^99mTc-SDF-1 has been used with single-photon emission computed tomography (SPECT) to determine changes in CXCR4 expression in the heart after a myocardial infarction. ⁶⁴Cu-1,1'-[1,4-Phenylenebis(methylene)]-bis[1,4,8,11-tetraazacyclotetradecane] (⁶⁴Cu-AMD3100), a bicyclam inhibitor of CXCR4 activity, has been studied in mice bearing orthotopic breast tumors and in mice with lung metastases with positron emission tomography (PET) (8). {N-[1,4,8,11-Tetraazacyclotetradecanyl-1,4-phenylenebis(methylene)]-2-(aminomethyl)pyridine} (AMD3465) is a monocyclam CXCR4 inhibitor with a ~15-fold higher affinity for CXCR4 than AMD3100. De Silva et al. (9) radiolabeled AMD3465 with ⁶⁴Cu to form ⁶⁴Cu-AMD3465 for PET imaging of CXCR4 expression in xenograft tumors in mice.

[PubMed]

AMD3465 (0.2 mg) was incubated with 370–740 MBq (10–20 mCi) ⁶⁴CuCl₂ in sodium acetate buffer (pH 5) for 45 min at 60°C (9). ⁶⁴Cu-AMD3465 was purified with high-performance liquid chromatography. This procedure provided a radiochemical purity of >98% with a specific activity of 6.0 ± 3.1 GBq/µmol (162 ± 84 mCi/µmol). The log P value for ⁶⁴Cu-AMD3465 was −2.71.

[PubMed]

A receptor-binding assay was performed with ¹²⁵I-SDF-1 (9). AMD3465 exhibited a 50% inhibition concentration (IC₅₀) value of 41.7 ± 1.2 nM. Cellular accumulation was performed using human glioblastoma U87 cells transfected with human CD4 and CXCR4 (U87-stb-CXCR4, 95% of cells positive for CXCR4), U87 cells (2% positive for CXCR4) and human colon HT-29 cells (low CXCR4 expression, 30% positive for CXCR4). These cells were incubated with ⁶⁴Cu-AMD3465 for 30 min at 4°C and then washed four times with cold binding medium. The amounts of radioactivity bound to U87-stb-CXCR4 cells, U87 cells, and HT-29 cells were 11%, 1%, and 2% incubation dose/10⁶ cells, respectively. Incubation of ⁶⁴Cu-AMD3465 with U87-stb-CXCR4 cells at 37°C showed a linear accumulation of radioactivity with the time of incubation. At 240 min of incubation, ~50% of radioactivity was internalized. No blocking studies were performed.

[PubMed]

No publication is currently available.

U24 CA92871

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De Silva R.A., Peyre K., Pullambhatla M., Fox J.J., Pomper M.G., Nimmagadda S. Imaging CXCR4 expression in human cancer xenografts: evaluation of monocyclam 64Cu-AMD3465. J Nucl Med. 2011;52(6):986–93. [PMC free article: PMC3155288] [PubMed: 21622896]