@article {Hillier1369, author = {Shawn M. Hillier and Kevin P. Maresca and Genliang Lu and Ross D. Merkin and John C. Marquis and Craig N. Zimmerman and William C. Eckelman and John L. Joyal and John W. Babich}, title = {99mTc-Labeled Small-Molecule Inhibitors of Prostate-Specific Membrane Antigen for Molecular Imaging of Prostate Cancer}, volume = {54}, number = {8}, pages = {1369--1376}, year = {2013}, doi = {10.2967/jnumed.112.116624}, publisher = {Society of Nuclear Medicine}, abstract = {Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer, and small-molecule radiopharmaceuticals targeting PSMA rapidly detect the location and extent of disease. Here we evaluated preclinically 4 novel 99mTc-labeled small-molecule inhibitors of PSMA with the potential for clinical translation for molecular imaging of prostate cancer in humans. Methods: Four PSMA inhibitors derived from the glutamate-urea-glutamate or glutamate-urea-lysine pharmacophores conjugated to CIM or TIM chelators were radiolabeled with 99mTc and evaluated in vitro and in vivo. Results: High-affinity, saturable binding to PSMA on LNCaP cells was observed with Kd values of 0.64 {\textpm} 0.46 nM for 99mTc-MIP-1427, 1.07 {\textpm} 0.89 nM for 99mTc-MIP-1404, 1.75 {\textpm} 0.32 nM for 99mTc-MIP-1428, and 4.35 {\textpm} 0.35 nM for 99mTc-MIP-1405. 99mTc-labeled PSMA inhibitors did not bind human prostate cancer PC3 cells, which lack PSMA, demonstrating specificity, and binding was abolished with 2-(phosphonomethyl)pentanedioic acid (PMPA), a structurally unrelated PSMA inhibitor. 99mTc-labeled PSMA inhibitors were shown to internalize at 37{\textdegree}C. Uptake in LNCaP xenografts ranged from 9.3\% to 12.4\% injected dose per gram at 1 h after injection and from 7.2\% to 11.0\% at 4 h, with tumor-to-blood ratios ranging from 29:1 to 550:1 and tumor{\textendash}to{\textendash}skeletal muscle ratios ranging from 31:1 to 157:1 at 4 h. 99mTc-MIP-1404 exhibited the best combination of high tumor uptake and rapid clearance from kidney and nontarget tissues. 99mTc-MIP-1404 specifically bound to PSMA in vivo as demonstrated by the absence of uptake in PC3 xenografts and by competition with PMPA. SPECT/CT imaging corroborated the tissue distribution results, demonstrating uptake only in PSMA-expressing kidney and tumor tissue and clearance through the urinary bladder. Conclusion: These 99mTc-labeled radiopharmaceuticals targeting PSMA may provide a SPECT molecular imaging option to assist in the initial diagnosis of prostate cancer and the management of patient care by monitoring disease progression.}, issn = {0161-5505}, URL = {https://jnm.snmjournals.org/content/54/8/1369}, eprint = {https://jnm.snmjournals.org/content/54/8/1369.full.pdf}, journal = {Journal of Nuclear Medicine} }