Preclinical evaluation of investigational radiopharmaceutical RISAD-pintended for use as a diagnostic and molecular radiotherapy agent for prostate cancer

BACKGROUND. The androgen receptor (AR) plays a dominant role in the pathogenesis of prostate cancer. 5-Radioiodo-30′-O- (17b-succinyl-5a-androstan-3-one)-20-deoxyuridin-50-yl phosphate (RISAD-P) is an AR-targeting reagent developed for noninvasive assessment of AR and proliferative status of the AR-expressing tumors, and for molecular radiotherapy with Auger electron-emitting radionuclides. In this study, the preclinical toxicity and targeting potential of RISAD-P was evaluated.

METHODS. Effects of nonradioactive ISAD-P and RISAD-P labeled with ¹²³I, ¹²⁴I, and ¹²⁵I were evaluated in male mice. Expanded-acute single dose toxicity studies, hematologic toxicity, liver and kidney function, pharmacokinetics, biodistribution, and imaging studies were conducted. Imaging and pilot therapy studies were conducted in transgenic mice.

RESULTS. RISAD-P is not toxic at doses projected for clinical use. Its tissue distribution compares favorably with the distribution reported for ¹⁸F-dihydrotestosterone derivatives. RISAD-P has excellent prostate cancer targeting properties. One hour after 125IRISAD-P administration, nearly 10% of the injected dose is associated with prostate tumor. The tumor clearance is biphasic and plateaus between 24 and 48 hr post-injection. The estimated radiation doses calculated for 1 g tumor using the MIRD convention are well within the therapeutic range with values of 170, 250, 1, 240 Gy × MBq^-1 × g^-1 for ¹²⁵I-, ¹²³I-, and ¹²⁴I-labeled RISAD-P, respectively. The transient uptake of radioactivity is observed in the genitourinary tract and stomach. Without the potassium iodide blockade, thyroid uptake is also observed.

CONCLUSIONS. Biodistribution, toxicity, and radiation dosimetry studies suggest that RISAD-P holds characteristics of a promising candidate for imaging of AR expression and tumor proliferation, as well as molecular radiotherapy for metastatic or locally, regionally advanced prostate cancer.