Szücs Dániel, Szabó Judit P, Arató Viktória, Gyuricza Barbara, Szikra Dezső, Tóth Imre, Képes Zita, Trencsényi György, Fekete Anikó
Division of Nuclear Medicine and Translational Imaging, Department of Medical Imaging, Faculty of Medicine, University of Debrecen, Nagyerdei krt. 98, H-4032 Debrecen, Hungary.
Department of Physical Chemistry, Faculty of Science and Technology, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary.
Pharmaceuticals (Basel). 2023 Sep 11;16(9):1280. doi: 10.3390/ph16091280.
Although radiolabeled alpha-melanocyte stimulating hormone-analogue NAPamide derivatives are valuable melanoma-specific diagnostic probes, their rapid elimination kinetics and high renal uptake may preclude them from being used in clinical settings. We aimed at improving the pharmacokinetics of radiolabeled DOTA-NAPamide compounds by incorporating a 4-(p-iodo-phenyl)-butanoic acid (IPB) into the molecules. Followed by Ga-, Bi-, and Lu-labelling, the radiopharmaceuticals ([Ga]Ga-DOTA-IPB-NAPamide, [Bi]Bi-DOTA-IPB-NAPamide, [Lu]Lu-DOTA-IPB-NAPamide) were characterized in vitro. To test the imaging behavior of the IPB-containing probes, B16F10 tumor-bearing C57BL/6 mice were subjected to in vivo microPET/microSPECT/CT imaging and ex vivo biodistribution studies. All tracers were stable in vitro, with radiochemical purity exceeding 98%. The use of albumin-binding moiety lengthened the in vivo biological half-life of the IPB-carrying radiopharmaceuticals, resulting in elevated tumor accumulation. Both [Ga]Ga-DOTA-IPB-NAPamide (5.06 ± 1.08 %ID/g) and [Bi]Bi-DOTA-IPB-NAPamide (4.50 ± 0.98 %ID/g) exhibited higher B16F10 tumor concentrations than their matches without the albumin-binding residue ([Ga]Ga-DOTA-NAPamide and [Bi]Bi-DOTA-NAPamide: 1.18 ± 0.27 %ID/g and 3.14 ± 0.32; respectively), however; the large amounts of off-target radioactivity do not confirm the benefits of half-life extension for short-lived isotopes. Enhanced [Lu]Lu-DOTA-IPB-NAPamide tumor uptake even 24 h post-injection proved the advantage of IPB-based prolonged circulation time regarding long-lived radionuclides, although the significant background noise must be addressed in this case as well.
尽管放射性标记的α-黑素细胞刺激激素类似物NAP酰胺衍生物是有价值的黑色素瘤特异性诊断探针，但其快速消除动力学和高肾脏摄取可能使其无法用于临床。我们旨在通过将4-(对碘苯基)-丁酸(IPB)纳入分子中来改善放射性标记的DOTA-NAP酰胺化合物的药代动力学。在进行Ga、Bi和Lu标记后，对放射性药物([Ga]Ga-DOTA-IPB-NAP酰胺、[Bi]Bi-DOTA-IPB-NAP酰胺、[Lu]Lu-DOTA-IPB-NAP酰胺)进行了体外表征。为了测试含IPB探针的成像行为，对荷B16F10肿瘤的C57BL/6小鼠进行了体内微型PET/微型SPECT/CT成像和体外生物分布研究。所有示踪剂在体外均稳定，放射化学纯度超过98%。白蛋白结合部分的使用延长了携带IPB的放射性药物的体内生物半衰期，导致肿瘤蓄积增加。[Ga]Ga-DOTA-IPB-NAP酰胺(5.06±1.08%ID/g)和[Bi]Bi-DOTA-IPB-NAP酰胺(4.50±0.98%ID/g)在B16F10肿瘤中的浓度均高于其不含白蛋白结合残基的对照物([Ga]Ga-DOTA-NAP酰胺和[Bi]Bi-DOTA-NAP酰胺：分别为1.18±0.27%ID/g和3.14±0.32%ID/g)，然而，大量的非靶向放射性并不能证实半衰期延长对短寿命同位素的益处。即使在注射后24小时，[Lu]Lu-DOTA-IPB-NAP酰胺的肿瘤摄取增强也证明了基于IPB的延长循环时间对长寿命放射性核素的优势，尽管在这种情况下也必须解决显著的背景噪声问题。
