Determination of pharmacokinetics and tissue distribution of a novel lutetium-labeled PSMA-targeted ligand, <SUP>177</SUP>Lu-DOTA-PSMA-GUL, in rats by using LC-MS/MS

초록

Prostate specific membrane antigen (PSMA) is known to be overexpressed in prostate cancer cells, providing as a diagnostic and therapeutic target for prostate cancer. A lutetium-labeled PSMA targeted ligand, Lu-177-DOTA-PSMA-GUL is a novel radiopharmaceutical, which has been developed for the treatment of prostate cancer. While the GUL domain of Lu-177-DOTA-PSMA-GUL binds to the antigen, the beta-emitting radioisotope, Lu-177-labeled DOTA, interacts with prostate cancer cells. However, the in vivo pharmacokinetics of intact Lu-177-DOTA-PSMA-GUL has never been characterized. This study aimed to evaluate the pharmacokinetics and tissue distribution of the radiopharmaceutical in rats by using its stable isotope-labeled analog, Lu-175-DOTA-PSMA-GUL. A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of Lu-175-DOTA-PSMA-GUL was developed and validated. Following intravenous injection, the plasma concentration-time profiles of Lu-175-DOTA-PSMA-GUL showed a multi-exponential decline with the average elimination half-life of 0.30 to 0.33 h. Systemic exposure increased with the dose and renal excretion is the major elimination route. Tissue distribution of Lu-175-DOTA-PSMA-GUL was most substantial in kidneys, followed by the prostate. The developed LC-MS/MS assay and the in vivo pharmacokinetic data of Lu-175-DOTA-PSMA-GUL would provide helpful information for further clinical studies to be developed as a novel therapeutic agent for prostate cancer.

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