Synthesis and Evaluation of ^99mTc-Tricabonyl Labeled Isonitrile Conjugates for Prostate-Specific Membrane Antigen (PSMA) Image

• Main Authors: Nadeem Ahmed Lodhi, Ji Yong Park, Kyuwan Kim, Mi Kyung Hong, Young Joo Kim, Yun-Sang Lee, Gi Jeong Cheon, Keon Wook Kang, Jae Min Jeong
• Format: Article
• Language: English
• Published: MDPI AG 2020-01-01
• Series: Inorganics
• Subjects: prostate cancer; prostate-specific membrane antigen; technetium-99m; spect; isonitrile
• Online Access: https://www.mdpi.com/2304-6740/8/1/5
• ISSN: 2304-6740

Prostate-specific membrane antigen (PSMA) is a biomarker expressed on the surface of prostate cancer (PCa). In an effort to improve the detection and treatment of PCa, small urea-based PSMA inhibitors have been studied extensively. In the present study, we aimed to develop ^99mTc-tricabonyl labeled urea-based PSMA conjugates containing isonitrile (CN-R)-coordinating ligands ([^99mTc]Tc-<b>15</b> and [^99mTc]Tc-<b>16</b>). Both the PSMA conjugates were obtained at high radiochemical efficiency (&#8805;98.5%). High in vitro binding affinity was observed for [^99mTc]Tc-<b>15</b> and [^99mTc]Tc-<b>16</b> (<i>K_d</i> = 5.5 and 0.2 nM, respectively) in PSMA-expressing 22Rv1 cells. Tumor xenografts were conducted using 22Rv1 cells and rapid accumulation of [^99mTc]Tc-<b>16</b> (1.87 &#177; 0.11% ID/g) was observed at 1 h post-injection, which subsequently increased to (2.83 &#177; 0.26% ID/g) at 4 h post-injection. However, [^99mTc]Tc-<b>15</b> showed moderate tumor uptake (1.48 &#177; 0.18% ID/g), which decreased at 4 h post-injection (0.81 &#177; 0.09% ID/g). [^99mTc]Tc-<b>16</b> was excreted from non-targeted tissues with high tumor-to-blood (17:1) and tumor-to-muscle ratio (41:1) at 4 h post-injection at approximately 4 times higher levels than [^99mTc]Tc-<b>15</b>. Uptakes of [^99mTc]Tc-<b>15</b> and [^99mTc]Tc-<b>16</b> to PSMA-expressing tumor and tissues were significantly blocked by co-injection of 2-(Phosphonomethyl)-pentandioic acid (2-PMPA), suggesting that their uptakes are mediated by PSMA specifically. Whole-body single photon emission computed tomography imaging of [^99mTc]Tc-<b>16</b> verified the ex vivo biodistribution results and demonstrated clear visualization of tumors and tissues expressing PSMA compared to [^99mTc]Tc-<b>15</b>. In conclusion, using [^99mTc]Tc-<b>16</b> rather than [^99mTc]Tc-<b>15</b> may be the preferable because of its relatively high tumor uptake and retention.