111In-Labeled Ac-TZ14011 peptide (a chemokine receptor 4 antagonist) conjugated to CyAL5.5 (a fluorescent dye) through a multifunctional single-attachment point (MSAP) reagent

Excerpt

The chemokine receptor 4 (CXCR4) and its ligand, the 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, these receptor–ligand pairs have a major role in the development, progression, and spread of various cancers (3), and the CXCR4 acts as a co-receptor to facilitate entry of the human immunodeficiency virus (HIV) into CD4⁺ cells (4). It has also been suggested that CXCR4 and SDF-1 participate in the pathogenesis of neurodegenerative and inflammatory conditions (5). The level of CXCR4 expression by tumor cells is considered to play a critical role in cancer metastasis by generating a chemotactic gradient to organs expressing the SDF-1, and the overexpression of CXCR4 in cancerous lesions indicates a poor prognosis for patients suffering from different types of cancer (6). The role of CXCR4 and SDF-1 for cancer metastasis is under investigation in several clinical trials approved by the United States Food and Drug Administration.

Because CXCR4 and SDF-1 are considered to play an important role in the development and progression of HIV infections and cancer, researchers have attempted to quantify CXCR4 levels with noninvasive imaging techniques for various pathological and physiological conditions (7). SDF-1 labeled with technetium (^99mTc) was used as a probe to determine changes in CXCR4 expression in the heart after a myocardial infarction, and it was concluded that the probe was suitable to visualize expression of the receptor in tissue with single-photon emission computed tomography (SPECT). In another study, copper (⁶⁴Cu)-labeled 1,1'-{1,4-phenylenebis(methylene)}-bis{1,4,8,11-tetraaza-cyclotetradecane} (AMD3100), an inhibitor of CXCR4 activity, was used for imaging and to study the biodistribution of the radiochemical with positron emission tomography in normal mice (8). This study showed that [⁶⁴Cu]AMD3100 accumulated mainly in the liver, kidneys, and spleen of the animals. An indium (¹¹¹In)-labeled CXCR4 antagonist peptide, [¹¹¹In]Ac-TZ14011, discussed in a separate chapter of MICAD (9), was developed for the scintigraphic imaging of xenograft tumors that express CXCR4 in mice, and its biodistribution was also investigated in the animals (10). A dual-imaging (multimodal imaging) probe has been generated by preparing a multifunctional single-attachment point (MSAP) reagent derivative of the Ac-TZ14011 peptide (11).

A characteristic feature of the MSAP reagent is that its structure contains a diethylenetriamine pentaacetic acid residue (for the chelation of a radionuclide such as ¹¹¹In) and a CyAL5.5 fluorescence dye residue (for fluorescence imaging; the excitation and emission maxima of this dye are 615–665 nm and 695–770 nm, respectively, similar to that of the Cy5.5 fluorescence dye). The dual-imaging probe was produced by conjugating the MSAP reagent with the Ac-TZ14011 peptide (Ac-TZ14011-MSAP), and the conjugate was labeled with ¹¹¹In to obtain the multimodal imaging agent ([¹¹¹In]Ac-TZ14011-MSAP) (11). The dual-labeled probe was evaluated for the imaging of xenograft tumors that overexpress the CXCR4 in mice, and its biodistribution was studied in the same animals (11).