Improving the biodistribution of PSMA‐targeting tracers with a highly negatively charged linker. Issue 7 (24th February 2014)

• Record Type: Journal Article
• Authors: Huang, Steve S.; Wang, Xinning; Zhang, Yuqing; Doke, Aniruddha; DiFilippo, Frank P.; Heston, Warren D.
• Is Part Of: Prostate. Volume 74:Issue 7(2014)
• Page Start: 702
• Page End: 713
• Publication Date: 2014-02-24
• Subjects: Prostate -- Diseases -- Periodicals; 616
• DOI: 10.1002/pros.22789
• Languages: English
• ISSNs: 0270-4137

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="pros22789-sec-0001" sec-type="section"> <title>BACKGROUND</title> <p>Prostate specific membrane antigen (PSMA) is overexpressed in prostate cancer and in tumor vasculature. Small molecule based inhibitors of PSMA have promised to provide sensitive detection of primary and metastatic prostate tumors. Although significant progress has been made, many of the radiolabeled imaging agents exhibit non‐specific background binding. Prevailing tracer designs focus on high affinity urea‐based inhibitors with strategically placed hydrophobic patches that interact favorably with the substrate tunnel of PSMA. We hypothesized that a novel PSMA inhibitor design incorporating highly negatively charged linkers may minimize non‐specific binding and decrease overall background.</p> </sec> <sec id="pros22789-sec-0002" sec-type="section"> <title>METHODS</title> <p>Through iterative redesign, we generated a series of PSMA inhibitors with highly negatively charged linkers that connect to urea inhibitors and bulky radionuclide chelates. We then performed in vivo imaging and biodistribution studies with the radiolabeled tracers.</p> </sec> <sec id="pros22789-sec-0003" sec-type="section"> <title>RESULTS</title> <p>The tracers derived from our iterative redesign have affinities for PSMA comparable to the "parent" urea ligand Cys‐C(O)‐Glu. Using a fluorine‐18 labeled PSMA targeting tracer, we found that these highly negatively charged molecules exhibit rapid renal excretion with minimal non‐specific binding. The biodistribution data at 2 hr showed 4.6%ID/g PC3‐PIP tumor uptake with spleen, liver, bone, and blood background levels of 0.1%, 0.17%, 0.1%, and 0.04%, respectively.</p> </sec> <sec id="pros22789-sec-0004" sec-type="section"> <title>CONCLUSION</title> <p>Placement of multiple negative charges in the linker region of PSMA tracers significantly reduced the non‐specific background binding without significant reduction of binding affinity. This increased tumor/background contrast in positron emission tomography promises to provide more sensitive tumor detection while decreasing the overall radiation exposure to patients. <italic>Prostate 74:702–713, 2014</italic>. © 2014 Wiley Periodicals, Inc.</p> </sec> </abstract>