Prostate-specific membrane antigen-based imaging

Abstract

Prostate cancer (CaP) is the most common noncutaneous malignancy affecting men in North America. Despite significant efforts, conventional imaging of CaP does not contribute to patient management as much as imaging performed for other common cancers. Given the lack of specificity in conventional imaging techniques, one possible solution is to screen for CaP-specific antigenic targets and generate agents able to specifically bind. Prostate-specific membrane antigen (PSMA) is overexpressed in CaP tissue, with low levels of expression in the small intestine, renal tubular cells, and salivary gland. The first clinical agent for targeting PSMA was (111)In-capromab, involving an antibody recognizing the internal domain of PSMA. The second- and third-generation humanized PSMA binding antibodies have the potential to overcome some of the limitations inherent to capromab penditide (i.e., inability to bind to live CaP cells). One example is the humanized monoclonal antibody J591 (Hu mAb J591) that was developed primarily for therapeutic purposes but also has interesting imaging characteristics, including the identification of bone metastases in CaP. The major disadvantage of use of mAb for imaging is slow target recognition and background clearance in an appropriate time frame for diagnostic imaging. Urea-based compounds, such as small molecule inhibitors may also present promising agents for CaP imaging with single-photon emission computed tomography (SPECT) and positron emission tomography (PET). Two such small-molecule inhibitors targeting PSMA, MIP-1072, and MIP-1095 have exhibited high affinity for PSMA. The uptake of (123)I-MIP-1072 and (123)I-MIP-1095 in CaP xenografts have imaged successfully with favorable properties amenable to human trials. While advances in conventional imaging will continue, Ab and small molecule imaging exemplified by PSMA targeting have the greatest potential to improve diagnostic sensitivity and specificity.

FIGURE 1

Structural elements of known PSMA substrate and inhibitors, compared with phosphoramidate (1). Highlighted portions indicate structural features similar to phosphoramidate design. Permission granted. THE JOURNAL OF NUCLEAR MEDICINE Vol. 50 No. 12 December 2009

FIGURE 2

(A) Anterior and Posterior planar ^99mTc-MDP Bone Scan demonstrating multifocal osseous metastasis. (B) Anterior and Posterior planar ¹⁷⁷Lu-huJ591demonstrating excellent tumor targeting to sites clearly seen on the bone scan and a few that are not clearly identified on bone scan. Abdominopelvic uptake was suspicious for soft tissue metastasis.

FIGURE 2

(A) Anterior and Posterior planar ^99mTc-MDP Bone Scan demonstrating multifocal osseous metastasis. (B) Anterior and Posterior planar ¹⁷⁷Lu-huJ591demonstrating excellent tumor targeting to sites clearly seen on the bone scan and a few that are not clearly identified on bone scan. Abdominopelvic uptake was suspicious for soft tissue metastasis.

FIGURE 3

Axial (top) and sagittal (bottom) reconstruction after treatment dose of ¹⁷⁷Lu-J591 SPECT/CT demonstrating localization in retroperitoneal lymph nodes as well as lumbar vertebrae.