Assessment of an 18F-labeled phosphoramidate peptidomimetic as a new prostate-specific membrane antigen-targeted imaging agent for prostate cancer.
Prostate-specific membrane antigen (PSMA) is a transmembrane protein commonly found on the surface of late-stage and metastatic prostate cancer and a well-known imaging biomarker for staging and monitoring therapy. Although (111)In-labeled capropmab pendetide is the only approved agent available for PSMA imaging, its clinical use is limited because of its slow distribution and clearance that leads to challenging image interpretation. A small-molecule approach using radiolabeled urea-based PSMA inhibitors as imaging agents has shown promise for prostate cancer imaging. The motivation of this work is to explore phosphoramidates as a new class of potent PSMA inhibitors to develop more effective prostate cancer imaging agents with improved specificity and clearance properties.


METHODS
N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB) was conjugated to S-2-((2-(S-4-amino-4-carboxybutanamido)-S-2-carboxyethoxy)hydroxyphosphorylamino)-pentanedioic acid (Phosphoramidate (1)), yielding S-2-((2-(S-4-(4-(18)F-fluorobenzamido)-4-carboxybutanamido)-S-2-carboxyethoxy)hydroxyphosphorylamino)-pentanedioic acid (3). In vivo studies were conducted in mice bearing either LNCaP (PSMA-positive) or PC-3 (PSMA-negative) tumors. PET images were acquired at 1 and 2 h with or without a preinjection of a nonradioactive version of the fluorophosphoramidate. Tissue distribution studies were performed at the end of the 2 h imaging sessions.


RESULTS
Phosphoramidate (1) and its fluorobenzamido conjugate (2) were potent inhibitors of PSMA (inhibitory concentration of 50% [IC(50)], 14 and 0.68 nM, respectively). PSMA-mediated tumor accumulation was noted in the LNCaP versus the PC-3 tumor xenografts. The LNCaP tumor uptake was also blocked by the administration of nonradioactive (2) prior to imaging studies. With the exception of the kidneys, tumor-to-tissue and tumor-to-blood ratios were greater than 5:1 at 2 h. The strong kidney uptake may be due to the known PSMA expression in the mouse kidney, because significant reduction (>6-fold) in kidney activity was seen in mice injected with (2).


CONCLUSIONS
(18)F-labeled phosphoramidate (3) is a representative of a new class of PSMA targeting peptidomimetic molecules that shows great promise as imaging agents for detecting PSMA+ prostate tumors.
Lapi
Suzanne E
SE
Department of Radiology and Biomedical Imaging, Center for Molecular and Functional Imaging, University of California, San Francisco, California 94107, USA.
Wahnishe
Hilla
H
Pham
David
D
Wu
Lisa Y
LY
Nedrow-Byers
Jessie R
JR
Liu
Tiancheng
T
Vejdani
Kaveh
K
VanBrocklin
Henry F
HF
Berkman
Clifford E
CE
Jones
Ella F
EF
D000577:Amides / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D010455:Peptides / Q000737:chemistry*; D010756:Phosphoric Acids / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D014018:Tissue Distribution
D000577:Amides; D000954:Antigens, Surface; D005462:Fluorine Radioisotopes; D010455:Peptides; D010756:Phosphoric Acids; C011067:phosphoramidic acid; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II