Intratumoral Distribution of [ ¹⁷⁷ Lu]Lu-PSMA-617 Over Time and in Relation to Diagnostic Tracers in Animal Models of Prostate Cancer

<b><i>Introduction:</i></b> Prostate-specific membrane antigen (PSMA) is a target for diagnostic positron emission tomography (PET)-tracers and radiopharmaceutical therapy (RPT), for example, [¹⁷⁷Lu]Lu-PSMA-617, in prostate cancer. This autoradiography study investigates [¹⁷⁷Lu]Lu-PSMA-617 intratumoral distribution over time, compared with PSMA expression, proliferation (Ki67), and [⁶⁸Ga]Ga-PSMA-11, [¹⁸F]F-PSMA-1007, [¹⁸F]-fluorodeoxyglucose, and [¹⁸F]-fluorocholine distribution. Mice with LNCaP, 22Rv1, or PC-3 PIP xenografts got [¹⁷⁷Lu]Lu-PSMA-617 i.v. Sacrificed 1 h p.i. if coinjected with diagnostic tracers, otherwise at 20 min, 1-2, 12, 24, 48, 72 h, or 2-3 weeks p.i. Cryosectioned tumors imaged by autoradiography, adjacent sections Ki67 or PSMA stained. <b><i>Results:</i></b> Heterogeneous distribution of [¹⁷⁷Lu]Lu-PSMA-617 was seen 20 min p.i., with visible overlap between tumor cells, Ki67, PSMA, and radioactivity at 1-2 h p.i. Strongest Ki67-correlation at 48 h, which became negative at 72 h and beyond with some Ki67+/PSMA+ low radioactivity areas. Uptake in necrotic tissue was only observed at 2-3 weeks p.i. PSMA-targeted tracers distributed identically to [¹⁷⁷Lu]Lu-PSMA-617 whereas other tracers only had some overlap. <b><i>Conclusion:</i></b> Regrowth of the tumor post-[¹⁷⁷Lu]Lu-PSMA-617 administration creates Ki67+/PSMA+ areas that have no radioactivity uptake and need additional therapy fractions. The identical intratumoral distribution of [¹⁷⁷Lu]Lu-PSMA-617 and PSMA-targeted PET-tracers indicate that these will reveal the areas inside the tumor targeted by RPT at least at 1 h p.i.