Download Molecular Imaging Probes of Prostate

Molecular Imaging Probes of Prostate-Specific Membrane Antigen (PSMA)
Prostate cancer (PCa) is the leading cancer in the U.S. population and the second
leading cause of cancer death in men. An estimated 241,740 new cases and 28,170 deaths
of PCa will occur in the US during 2012, according to the statistics of American Cancer
Society. Current early detection methods of PCa are prostate specific antigen (PSA) in the
blood and digital rectal exam. But PSA is not specific for PCa. That lack of specificity
accounts for unnecessary biopsies or treatment of what would be benign or indolent
disease.
Although no single biomarker is capable of distinguishing tumor regions from indolent sites,
the prostate-specific membrane antigen (PSMA), a type II integral membrane protein
overexpressed on PCa, provides a step in that direction. Both disease-free survival and time
to PSA progression are decreased in patients with elevated levels of PSMA within their
tumors.
PCa are not visualized as obviously as solid tumors by the scanning of positron
emission tomography (PET) with [18F]-fluorodeoxyglucose ([18F]-FDG), the gold standard
radiopharmaceutical in clinic, because PCa tends to grow slowly and is less metabolically
active. SPECT-CT imaging of PCa using [111In]capromab pendetide (ProstaScint™), an 111Inlabeled monoclonal antibody to PSMA, received approval by FDA and has shown promise in
the clinic. However, the antibody-based imaging agent exhibited poor pharmacokinetic
properties in clinic. To overcome the drawback of the antibody-based imaging probe, we
have developed low M.W. imaging agents targeting PSMA for the diagnosis of metastatic
PCa.
A series of urea-derived PSMA inhibitors labeled with 125I, 18F, 99mTc, 111In, or
optical dyes were designed, synthesized and evaluated. Some of them showed the excellent
properties for PSMA imaging from the in vivo animal studies as well as the in vitro and ex
vivo biodistribution experiments. Several compounds have been successfully filed as
investigational new drug (IND) for the human clinical studies. Design concepts, synthetic
strategies and biological evaluations of the PSMA-based imaging agents will be discussed in
detail.