Kanellopoulos Panagiotis, Nock Berthold A, Krenning Eric P, Maina Theodosia
Molecular Radiopharmacy, INRaSTES, NCSR "Demokritos", 15341 Athens, Greece.
Cyclotron Rotterdam BV, Erasmus MC, 3015 CE Rotterdam, The Netherlands.
Pharmaceutics. 2023 Aug 7;15(8):2092. doi: 10.3390/pharmaceutics15082092.
The neurotensin subtype 1 receptor (NTSR) is overexpressed in a number of human tumors, thereby representing a valid target for cancer theranostics with radiolabeled neurotensin (NT) analogs like [Tc]Tc-DT1 (DT1, N-Gly-NT(8-13)). Thus far, the fast degradation of intravenously injected NT-radioligands by neprilysin (NEP) and angiotensin-converting enzyme (ACE) has compromised their clinical applicability. Aiming at metabolic stability enhancements, we herein introduce (i) DT7 ([DAsn]DT1) and (ii) DT8 ([β-Homoleucine]DT1), modified at the C-terminus, along with (iii) DT9 ([(palmitoyl)Lys]DT1), carrying an albumin-binding domain (ABD) at Lys. The biological profiles of the new [Tc]Tc-radioligands were compared with [Tc]Tc-DT1, using NTSR-expressing AsPC-1 cells and mice models without or during NEP/ACE inhibition. The radioligands showed enhanced in vivo stability vs. [Tc]Tc-DT1, with [Tc]Tc-DT9 displaying full resistance to both peptidases. Furthermore, [Tc]Tc-DT9 achieved the highest cell internalization and tumor uptake even without NEP/ACE-inhibition but with unfavorably high background radioactivity levels. Hence, unlike C-terminal modification, the introduction of a pendant ABD group in the linker turned out to be the most promising strategy toward metabolic stability, cell uptake, and tumor accumulation of [Tc]Tc-DT1 mimics. To improve the observed suboptimal pharmacokinetics of [Tc]Tc-DT9, the replacement of palmitoyl on Lys by other ABD groups is currently being pursued.
神经降压素1型受体（NTSR）在多种人类肿瘤中过度表达，因此成为使用放射性标记的神经降压素（NT）类似物如[锝]Tc-DT1（DT1，N-甘氨酰-NT(8-13)）进行癌症诊疗的有效靶点。到目前为止，静脉注射的NT放射性配体被中性内肽酶（NEP）和血管紧张素转换酶（ACE）快速降解，这限制了它们的临床应用。为了提高代谢稳定性，我们在此引入了（i）DT7（[DAsn]DT1）和（ii）DT8（[β-高亮氨酸]DT1），它们在C端进行了修饰，以及（iii）DT9（[(棕榈酰)赖氨酸]DT1），其在赖氨酸处带有白蛋白结合域（ABD）。使用表达NTSR的AsPC-1细胞以及在无NEP/ACE抑制或有NEP/ACE抑制的小鼠模型，将新的[锝]Tc放射性配体的生物学特性与[锝]Tc-DT1进行了比较。这些放射性配体在体内的稳定性比[锝]Tc-DT1有所提高，其中[锝]Tc-DT9对两种肽酶均表现出完全抗性。此外，即使在没有NEP/ACE抑制的情况下，[锝]Tc-DT9也实现了最高的细胞内化和肿瘤摄取，但背景放射性水平较高，这并不理想。因此，与C端修饰不同，在连接子中引入一个侧链ABD基团被证明是提高[锝]Tc-DT1类似物代谢稳定性、细胞摄取和肿瘤蓄积的最有前景的策略。为了改善观察到的[锝]Tc-DT9欠佳的药代动力学，目前正在探索用其他ABD基团取代赖氨酸上的棕榈酰基。
