Reshaping [^99mTc]Tc-DT11 to DT14D Tagged with Trivalent Radiometals for NTS₁R-Positive Cancer Theranostics

Area of Science:

• Radiochemistry
• Oncology
• Molecular Imaging

Background:

• Neurotensin subtype 1 receptor (NTS1R)-expressing tumors (pancreatic, gastrointestinal, prostate) are targets for radiotheranostics.
• Fast degradation of neurotensin (NT)-based radioligands by proteases limits efficacy.
• Previous DT11 showed promise but DT14D offers broader theranostic potential with DOTA chelator.

Purpose of the Study:

• To evaluate DT14D, a modified NT analog with a DOTA chelator, for radiotheranostic applications.
• To assess the stability and tumor-targeting capabilities of DT14D labeled with various radiometals.
• To determine if DT14D retains the enhanced metabolic stability of DT11.

Main Methods:

• DT14D was labeled with Ga-67, In-111, and Lu-177.
• Radioligands were tested for affinity and internalization in NTS1R-expressing AsPC-1 cells.
• In vivo studies were conducted in NTS1R-positive AsPC-1 xenograft mouse models.

Main Results:

• [Ga-67]Ga/[In-111]/[Lu-177]-DT14D demonstrated high affinity for NTS1R and cellular internalization.
• Radioligands remained over 70% intact in circulation 5 minutes post-injection in mice.
• Specific NTS1R-mediated uptake was observed in AsPC-1 tumor xenografts.

Conclusions:

• Modified NT analogs like DT14D exhibit enhanced metabolic stability.
• DT14D shows significant potential for radiotheranostic applications in NTS1R-positive cancers.
• The DOTA chelator enables versatile radiometal labeling for diverse theranostic uses.