A phosphoramidate-based prostate-specific membrane antigen-targeted SPECT agent.
BACKGROUND
Prostate-specific membrane antigen (PSMA) remains an active target for imaging and therapeutic applications for prostate cancer.


METHODS
In the present study, an irreversible phosphoramidate inhibitor, CTT-54 (IC50 = 14 nM), has been modified to deliver 99mTc-(CO)3-DTPA as a SPECT imaging payload to PSMA+ cells in vivo and in vitro. Percent uptake, competitive binding, and internalization will evaluate the imaging agent in vitro. Preliminary biodistribution and imaging will be utilized for in vivo evaluation.


RESULTS
In vitro studies demonstrate that the radiotracer 99mTc-(CO)3-DTPA-CTT-54 exhibits increasing cellular uptake in the PSMA+ LNCaP cells over time. More importantly, it was found that 99mTc-(CO)3-DTPA-CTT-54 is rapidly internalized into LNCaP cells, presumably through the PSMA enzyme-inhibitor complex. In a pilot biodistribution study, increasing accumulation of the radiotracer in LNCaP xenografts was observed from 2 to 4 hr and significant clearance from non-target tissues.


CONCLUSIONS
While DTPA may not represent the ideal chelate structure for 99mTc(CO)3, the data provides proof-of-concept support for the development of a next-generation phosphoramidate-based PSMA inhibitor-conjugates for use as SPECT imaging agents.
Department of Chemistry,Washington State University, Pullman, Washington 99164-4630, USA.
Jessie R
JR
Nedrow-Byers
Mohamed
M
Jabbes
Cayla
C
Jewett
Tanushree
T
Ganguly
Haiyang
H
He
Tiancheng
T
Liu
Paul
P
Benny
Jeffrey N
JN
Bryan
Clifford E
CE
Berkman
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000577:Amides / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008819:Mice, Nude; D004369:Pentetic Acid / Q000378:metabolism; D010756:Phosphoric Acids / Q000378:metabolism*; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D012680:Sensitivity and Specificity; D013667:Technetium / Q000378:metabolism; D013997:Time Factors; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*; D014183:Transplantation, Heterologous
D000577:Amides; D010756:Phosphoric Acids; D013667:Technetium; D004369:Pentetic Acid; C011067:phosphoramidic acid; D017430:Prostate-Specific Antigen