Martin Sebastian, Schreck Moritz-Valentin, Stemler Tobias, Maus Stephan, Rosar Florian, Burgard Caroline, Schaefer-Schuler Andrea, Ezziddin Samer, Bartholomä Mark D
Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital, Rue de Bugnon 25A, 1011, Lausanne, Switzerland.
Department of Nuclear Medicine, Saarland University - Medical Center, Kirrbergerstrasse, 66421, Homburg, Germany.
EJNMMI Radiopharm Chem. 2024 Dec 11;9(1):84. doi: 10.1186/s41181-024-00314-7.
The NOTI chelating scaffold can readily be derivatized for bioconjugation without impacting its metal complexation/radiolabeling properties making it an attractive building block for the development of multimeric/-valent radiopharmaceuticals. The objective of the study was to further explore the potential of the NOTI chelating platform by preparing and characterizing homotrimeric PSMA radioconjugates in order to identify a suitable candidate for clinical translation.
Altogether, three PSMA conjugates based on the NOTI-TVA scaffold with different spacer entities between the chelating unit and the Glu-CO-Lys PSMA binding motif were readily prepared by solid phase-peptide chemistry. Cell experiments allowed the identification of the homotrimeric conjugate 9 comprising NaI-Amc spacer with high PSMA binding affinity (IC = 5.9 nM) and high PSMA-specific internalization (17.8 ± 2.5%) compared to the clinically used radiotracer [Ga]Ga-PSMA-11 with a IC of 18.5 nM and 5.2 ± 0.2% cell internalization, respectively. All Ga-labeled trimeric conjugates showed high metabolic stability in vitro with [Ga]Ga-9 exhibiting high binding to human serum proteins (> 95%). Small-animal PET imaging revealed a specific tumor uptake of 16.0 ± 1.3% IA g and a kidney uptake of 67.8 ± 8.4% IA g for [Ga]Ga-9. Clinical PET imaging allowed identification of all lesions detected by [Ga]Ga-PSMA-11 together with a prolonged blood circulation as well as a significantly lower kidney and higher liver uptake of [Ga]Ga-9 compared to [Ga]Ga-PSMA-11.
Trimerization of the Glu-CO-Lys binding motif for conjugate 9 resulted in a ~ threefold higher binding affinity and cellular uptake as well as in an altered biodistribution profile compared to the control [Ga]Ga-PSMA-11 due to its intrinsic high binding to serum proteins. To fully elucidate its biodistribution, future studies in combination with long-lived radionuclides, such as Cu, are warranted. Its prolonged biological half-life and favorable tumor-to-kidney ratio make this homotrimeric conjugate also a potential candidate for future radiotherapeutic applications in combination with therapeutic radionuclides such as Cu.
NOTI螯合支架可轻松衍生用于生物共轭，而不影响其金属络合/放射性标记特性，这使其成为开发多聚体/多价放射性药物的有吸引力的构建模块。本研究的目的是通过制备和表征同三聚体PSMA放射性缀合物，进一步探索NOTI螯合平台的潜力，以确定适合临床转化的候选物。
通过固相肽化学方法，共制备了三种基于NOTI-TVA支架的PSMA缀合物，螯合单元与Glu-CO-Lys PSMA结合基序之间具有不同的间隔基团。细胞实验表明，同三聚体缀合物9包含NaI-Amc间隔基团，与临床使用的放射性示踪剂[Ga]Ga-PSMA-11相比，具有高PSMA结合亲和力（IC = 5.9 nM）和高PSMA特异性内化（17.8±2.5%），[Ga]Ga-PSMA-11的IC为18.5 nM，细胞内化率为5.2±0.2%。所有Ga标记的三聚体缀合物在体外均表现出高代谢稳定性，[Ga]Ga-9与人血清蛋白的结合率高（>95%）。小动物PET成像显示，[Ga]Ga-9的肿瘤特异性摄取为16.0±1.3%IA g，肾脏摄取为67.8±8.4%IA g。临床PET成像显示，[Ga]Ga-9能够识别[Ga]Ga-PSMA-11检测到的所有病变，且血液循环时间延长，与[Ga]Ga-PSMA-11相比，肾脏摄取显著降低，肝脏摄取增加。
与对照[Ga]Ga-PSMA-11相比，缀合物9的Glu-CO-Lys结合基序三聚化导致结合亲和力和细胞摄取提高约三倍，且由于其与血清蛋白的固有高结合力，生物分布特征发生改变。为了充分阐明其生物分布，未来有必要结合长寿命放射性核素（如Cu）进行研究。其延长的生物半衰期和良好的肿瘤与肾脏摄取比值，也使这种同三聚体缀合物成为未来与治疗性放射性核素（如Cu）联合进行放射治疗应用的潜在候选物。
