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

Area of Science:

• Nuclear medicine
• Radiopharmaceutical chemistry
• Oncology

Background:

• Prostate-specific membrane antigen (PSMA)-targeting agents are crucial for diagnosing and treating PSMA-positive metastatic castration-resistant prostate cancer (mCRPC).
• Neuroendocrine-differentiated prostate cancer (NEPC), an aggressive subtype, often exhibits reduced PSMA expression, evading current PSMA-targeted diagnostics and therapies.
• Somatostatin receptor 2 (SSTR2) ligands show elevated uptake in PSMA-negative NEPC, suggesting SSTR2 as a potential therapeutic target.

Purpose of the Study:

• To design and synthesize novel dual-targeting radiotracers combining PSMA-targeting ligands with an SSTR2-targeting peptide.
• To evaluate the diagnostic and therapeutic potential of these novel agents for NEPC.

Main Methods:

• Synthesis of dual-targeting radiotracers [⁶⁸Ga]Ga-1 and [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-2 by conjugating SSTR2-targeting peptide JR11 with PSMA-targeting ligands P16-093 and P17-087.
• In vitro cell uptake studies in PSMA-positive and SSTR2-positive cell lines.
• In vivo studies using tumor-bearing mice (SSTR2+ or PSMA+) to assess tumor uptake and targeting efficacy.

Main Results:

• [⁶⁸Ga]Ga-1 demonstrated comparable cell uptake to [⁶⁸Ga]Ga-P16-093 in PSMA-positive cells.
• [⁶⁸Ga]Ga-1 and [⁶⁸Ga]Ga-2 showed positive, albeit slightly lower, uptake than [⁶⁸Ga]Ga-DOTA-TATE in SSTR2-positive cells.
• In vivo studies confirmed positive uptake of both radiotracers in both SSTR2+ and PSMA+ tumors.

Conclusions:

• The developed dual-targeting radiotracers ([⁶⁸Ga]Ga-1 and [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-2) effectively target both SSTR2 and PSMA.
• These agents hold significant potential for improving the diagnosis and radioligand therapy of neuroendocrine-differentiated prostate cancer.