Reshaping [Tc]Tc-DT11 to DT14D Tagged with Trivalent Radiometals for NTSR-Positive Cancer Theranostics.

: Radiotheranostics of neurotensin subtype 1 receptor (NTSR)-expressing tumors, like pancreatic, gastrointestinal, or prostate cancer, has attracted considerable attention in recent years. Still, the fast degradation of neurotensin (NT)-based radioligands, by angiotensin-converting enzyme (ACE), neprilysin (NEP), and other proteases, has considerably compromised their efficacy. The recently introduced [Tc]Tc-DT11 (DT11, N-Lys(MPBA-PEG4)-Arg-Arg-Pro-Tyr-Ile-Leu-OH; N, 6-(carboxy)-1,4,8,11-tetraazaundecane) has displayed promising uptake in NTSR-positive tumors in mice and enhanced resistance to both ACE and NEP by virtue of the lateral MPBA-PEG4 (MPBA, 4-(4-methylphenyl)butyric acid; PEG4, 14-amino-3,6,9,12-tetraoxatetradecan-1-oic acid) chain attached to the ε-NH of Lys. We were next interested in investigating whether these qualities could be retained in DT14D, likewise modified at Lys but carrying the universal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) via a (βAla) spacer at the α-NH of Lys. This chelator switch enables the labeling of DT14D with a wide range of trivalent radiometals suitable for true theranostic applications, not restricted to the diagnostic imaging of NTSR-positive lesions only by single-photon emission computed tomography (SPECT). : DT14D was labeled with Ga-67 (a surrogate for the positron emission tomography radionuclide Ga-68), In-111 (for SPECT), and Lu-177 (applied in radiotherapy). The resulting radioligands were tested in NTSR-expressing pancreatic cancer AsPC-1 cells and mice models. : [Ga]Ga/[In]In/[Lu]Lu-DT14D displayed high affinity for human NTSR and internalization in AsPC-1 cells. They remained >70% intact 5 min after entering the mice's circulation, displaying NTSR-specific uptake in AsPC-1 xenografts. : Suitably side-chain modified NT analogs show enhanced metabolic stability and hence better prospects for radiotheranostic application in NTSR-positive cancer.