123I-Labeled (S)-2-(3-((S)-1-carboxy-5-(3-(4-iodophenyl) ureido)pentyl)ureido)pentanedoic acid

Excerpt

The prostate-specific membrane antigen (PSMA), a membrane-bound glycoprotein that possesses different peptidase activities (see Table above), is expressed mainly in the prostate epithelium. Because of its overexpression in primary, metastatic or hormone-refractory prostate and other cancers, including the neovasculature of solid tumors, this antigen is considered to be a cancer marker and a good target for imaging agents and therapy (1). Hence, PSMA has been targeted in several clinical trials that have been approved by the United States Food and Drug Administration (FDA) for the treatment of prostate cancer. In addition, capromab pendetide, a commercially available monoclonal antibody (MAb) that binds to the intracellular domain of the PSMA and was approved by the FDA for the diagnostic imaging of prostate cancer, has limited use because the MAb binds primarily to necrotic parts of the tumor and may not detect any viable malignant tumor cells (2). Investigators have also developed and evaluated MAbs directed against the extracellular domains of PSMA, and after preclinical studies they reported that these MAbs could be of potential use in the detection and treatment of PSMA-positive cancers (3-5). However, results obtained from a phase I clinical trial to evaluate the use of ¹¹¹In-labeled/unlabeled J591 MAb mixture to detect and target the PSMA-positive vasculature of progressive solid tumors in patients with breast, colon, liver, or kidney cancers showed that, although the antibody was well tolerated, selectively targeted a variety of solid tumors, but it did not yield any positive therapeutic response(s) (6). The investigators concluded that this was probably because the large molecular size of the MAb was a hindrance to its complete penetration into the tumors. In addition, therapeutic MAbs have poor pharmacokinetic profiles in normal tissues because they have an extended circulation period compared with the small molecule drugs.

Radiolabeled small molecule drugs have an advantage over MAbs because they are inexpensive to produce, can easily penetrate solid tumors, and, due to their pharmacokinetic properties, are superior for use in the detection (by imaging techniques) and therapy of cancerous tumors. On the basis of the facts presented above, a series of small-molecule inhibitors of PSMA were recently synthesized for possible use in conjunction with single-photon emission computed tomography/computed tomography (SPECT/CT) for the detection and staging of prostate cancer (7). Two of these compounds, (S)-2-(3-((S)-1-carboxy-5-(3-(4-iodophenyl)ureido)pentyl)ureido)pentanedoic acid (MIP-1095) and (S)-2-(3-((S)-1-carboxy-5-(3-(4-iodobenzylamino)pentyl)ureido)pentanedoic acid (MIP-1072), were labeled with ¹²³I by Hillier et al. for evaluation as molecular imaging agents to detect prostate cancer in a mouse model (8). This chapter describes the studies performed with [¹²³I]MIP-1095 under in vitro conditions and its biodistribution in mice bearing LNCaP (derived from human metastatic prostate carcinoma; expresses PSMA) and PC (developed from the bone marrow of a patient with secondary myelodisplastic syndrome; does not express PSMA; for further details regarding this cell line please see (9)) cell xenograft tumors. Studies performed with [¹²³I]MIP-1072 are presented in a separate chapter in MICAD (www.micad.nih.gov) (10).