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

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, ¹⁷⁷Lu-DOTA-PSMA-GUL is a novel radiopharmaceutical, which has been developed for the treatment of prostate cancer. While the GUL domain of ¹⁷⁷Lu-DOTA-PSMA-GUL binds to the antigen, the beta-emitting radioisotope, ¹⁷⁷Lu-labeled DOTA, interacts with prostate cancer cells. However, the in vivo pharmacokinetics of intact ¹⁷⁷Lu-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, ¹⁷⁵Lu-DOTA-PSMA-GUL. A sensitive liquid chromatography-tandem mass spectrometry (LC–MS/MS) analysis of ¹⁷⁵Lu-DOTA-PSMA-GUL was developed and validated. Following intravenous injection, the plasma concentration–time profiles of ¹⁷⁵Lu-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 ¹⁷⁵Lu-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 ¹⁷⁵Lu-DOTA-PSMA-GUL would provide helpful information for further clinical studies to be developed as a novel therapeutic agent for prostate cancer.