Cu-1,4,7-Triazacyclononane-1,4,7-triacetic acid-Arg-Arg-Natl-Cys-Tyr-Cit-Lys-d-Lys-Pro-Tyr-Arg-Cit-Cys-Arg-NH

Chemokine receptors are G-protein–coupled receptors directing cell movement 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 CXCR4 acts as a co-receptor for human immunodeficiency virus (HIV) on CD4 T cells (4). It has been suggested that CXCR4/SDF-1 interaction contributes to 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. It is critical to perform imaging studies to measure CXCR4 levels under conditions for various pathological and physiological conditions (7). Tc-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. Cu-1,1'-[1,4-Phenylenebis(methylene)]-bis[1,4,8,11-tetraaza-cyclotetradecane] (Cu-AMD3100), an inhibitor of CXCR4 activity, has been studied with positron emission tomography (PET) (8). An In-labeled CXCR4 antagonist peptide, In-Ac-TZ14011, has been developed for SPECT imaging of CXCR4 expression in xenograft tumors in mice (9). Tamamura et al. (10) identified TN14003, a 14-amino-acid peptide (Arg-Arg-Natl-Cys-Tyr-Cit-Lys-d-Lys-Pro-Tyr-Arg-Cit-Cys-Arg-NH) with high anti-HIV and CXCR4 antagonistic activities . Jacobson et al. (11) radiolabeled TN14003 with 4-[F]fluorobenzoic acid ([F]FBA) to form 4-[F]fluorobenzoyl-Arg-Arg-Natl-Cys-Tyr-Cit-Lys-d-Lys-Pro-Tyr-Arg-Cit-Cys-Arg-NH (4-[F]F-T140) for PET imaging of tumor CXCR4 expression with a high tumor/background ratio. However, 4-[F]F-T140 exhibited high nonspecific accumulation in red blood cells (RBCs), which masked its binding to CXCR4 on tumors. Later, Jacobson et al. (12) replaced 4-fluorobenzoyl in T140 with 1,4,7,10-tetraazacyclododecane-,','','''-1,4,7,10-tetraacetic acid (DOTA) to form DOTA-NFB or 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) to form NOTA-NFB for radiolabeling with Cu. Cu-DOTA-NFB and Cu-NOTA-NFB showed higher tumor/background ratios than 4-[F]F-T140 with lower bindings to RBCs.