PSMA and SSTR2 Dual-Targeting Theranostic Agents for Neuroendocrine-Differentiated Prostate Cancer (NEPC)

Radioactive prostate-specific membrane antigen (PSMA)-targeting agents are clinically useful for the diagnosis and treatment of patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). Neuroendocrine-differentiated prostate cancer (NEPC), a highly aggressive subtype that is strongly associated with a poor clinical prognosis, may present with reduced PSMA expression and evade detection with PSMA-targeted agents. Several studies have shown elevated uptake of somatostatin receptor 2 (SSTR2) ligands in PSMA-negative NEPC. By combining a SSTR2-targeting peptide, JR11, with previously reported PSMA-targeting ligands, P16-093 and P17-087, [⁶⁸Ga]Ga-<b>1</b> and [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-<b>2</b> were designed and synthesized. The cell uptake of [⁶⁸Ga]Ga-<b>1</b> was comparable to [⁶⁸Ga]Ga-P16-093 in PSMA-positive cell lines, while [⁶⁸Ga]Ga-<b>1</b> and [⁶⁸Ga]Ga-<b>2</b> showed a positive but slightly lower uptake than [⁶⁸Ga]Ga-DOTA-TATE in SSTR2-positive cell lines. In vivo studies in SSTR2+ or PSMA+ tumor-bearing mice demonstrated that [⁶⁸Ga]Ga-<b>1</b> and [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-<b>2</b> showed positive uptake for both SSTR2+ and PSMA+ tumors. These dual-targeting radiotracers are potentially valuable for the diagnosis and radioligand therapy of NEPC.