Excerpt

Optical fluorescence imaging is increasingly being used to monitor biological functions of specific targets in small animals (1-3). However, the intrinsic fluorescence of biomolecules poses a problem when fluorophores that absorb visible light (350–700 nm) are used. Near-infrared (NIR) fluorescence (700–1,000 nm) detection avoids the natural background fluorescence interference of biomolecules, providing a high contrast between target and background tissues in small animals. NIR fluorophores have a wider dynamic range and minimal background fluorescence as a result of reduced scattering compared with visible fluorescence detection. NIR fluorophores also have high sensitivity, attributable to low background fluorescence, and high extinction coefficients, which provide high quantum yields. The NIR region is also compatible with solid-state optical components, such as diode lasers and silicon detectors. NIR fluorescence imaging is a non-invasive alternative to radionuclide imaging in small animals (4, 5). Prostate-specific membrane antigen (PSMA) is a cell-surface glycoprotein with a molecular weight of ~100 kDa. It is a unique, type II, transmembrane-bound glycoprotein that is overexpressed on prostate tumor cells and in the neovasculature of most solid prostate tumors, but not in the vasculature of normal tissues (6, 7). PSMA has also been detected in other tissues such as the kidneys, the proximal small intestine, and the salivary glands (7). PSMA was found to have N-acetyl α-linked acidic dipeptidase (NAALADase) or glutamate carboxypeptidase II activity (8). PSMA may play an important role in the progression of prostate cancer and glutamatergic neurotransmission, as well as in the absorption of folate (9). In the central nervous system, PSMA metabolizes N-acetyl-aspartyl-glutamate, and in the proximal small intestine it removes γ-linked glutamates from poly-γ-glutamate folate and folate hydrolase (7). PSMA can be used as a marker for the detection of metastatic cancers with imaging agents. Although a commercially available monoclonal antibody (111In-labeled Capromomab pendetide (111In-CYT-356)) is in clinical use for the detection of prostate cancer, the results obtained with this antibody are not entirely reliable (10). In addition, this antibody has limited access to tumors and may produce low signal/noise ratios because the target is the intracellular domain of PSMA (11, 12). 2-(3-{5-[7-(5-Amino-1-carboxy-pentylcarbamoyl)-heptanoylamino]-1-carboxy-pentyl}-ureido)-pentanedioic acid (YC-27) was conjugated with IRDye800CW to form IRDye800-YC-27 (13), which is an inhibitor of NAALADase. IRDye800-YC-27 has been studied for use as an NIR agent for imaging PSMA expression in nude mice bearing human cancer xenografts.