最近，许多放射性金属化肽已被批准用于多种癌症的临床成像和/或治疗（治疗学），然而，大多数肽面临的主要挑战是显著的肾脏摄取和保留，这通常是剂量限制因素，并可能导致肾毒性。为应对这一问题，已采用多种方法来减少肾脏对放射性金属化肽的摄取，其中之一就是添加链节来调节极性和/或电荷。为了更好地了解净电荷对放射性金属化肽生物分布的影响，我们选择了临床上流行的构造物DOTA-TATE（NETSPOT/LUTATHERA）作为模型系统。我们使用手动固相肽合成方法合成了衍生物，包括机械和超声波搅拌，成功制备了金标准的DOTA-TATE和一系列具有不同净电荷（+2、+1、0、-1、-2）的衍生物。对健康雌性小鼠（CD1）进行的0到90分钟的动态PET成像显示，净中性（0）电荷的[68Ga]Ga-DOTA-TATE在肾脏有高积累和保留，并且正电荷衍生物的积累更高，而负电荷衍生物则表现出低积累和快速肾排泄。注射后2小时的体外生物分布表明，[68Ga]Ga-DOTA-TATE（约74％ID / g）在肾脏中有显著积累，并随着每个分子的净正电荷增加到+1和+2而增加（约272％ID / g和约333％ID / g），但净负电荷分子则表现出较低的肾脏摄取（约15％ID / g和16％ID / g）。有趣的是，净-2电荷的[68Ga]Ga-DOTA-(Glu)2-PEG4-TATE在血清中稳定，但健康器官摄取（肺、肝、脾）却比净-1化合物高得多，表明该化合物在体内不稳定。虽然净电荷为0的[68Ga]Ga-DOTA-PEG4-TATE衍生物也显示出肾脏摄取减少，但在血清和体内也表现出不稳定性。尽管净电荷为-1的[68Ga]Ga-DOTA-Glu-PEG4-TATE在健康小鼠中相对于肾脏摄取和整体特性有卓越的药代动力学，但在携带AR42J（SSTR2过度表达）皮下肿瘤移植的雄性小鼠（NSG）的动态PET图像和体外生物分布中，肿瘤摄取明显降低，与金标准的[68Ga]Ga-DOTA-TATE相比。总之，这些发现明确表明，肽基放射性追踪剂的净电荷显著影响肾脏摄取和保留。此外，显示负电荷的肽显著降低肾脏摄取，但在此实例中肿瘤摄取也受到影响。

Recently, several radiometalated peptides have been approved for clinical imaging and/or therapy (theranostics) of several types of cancer; nonetheless, the primary challenge that most of these peptides confront is significant renal uptake and retention, which is often dose limiting and can cause nephrotoxicity. In response to this, numerous methods have been employed to reduce the uptake of radiometalated peptides in the kidneys, and among these is adding a linker to modulate polarity and/or charge. To better understand the influence of net charge on the biodistribution of radiometalated peptides, we selected the clinically popular construct DOTA-TATE (NETSPOT/LUTATHERA) as a model system. We synthesized derivatives using manual solid-phase peptide synthesis methods including mechanical and ultrasonic agitation to effectively yield the gold standard DOTA-TATE and a series of derivatives with different net charges (+2, +1, 0, -1, -2). Dynamic PET imaging from 0 to 90 min in healthy female mice (CD1) revealed high accumulation and retention of activity in the kidneys for the net-neutral (0) charged [68Ga]Ga-DOTA-TATE and even higher for positively charged derivatives, whereas negatively charged derivatives exhibited low accumulation and fast renal excretion. Ex vivo biodistribution at 2 h post injection demonstrated a significant retention of [68Ga]Ga-DOTA-TATE (∼74 %ID/g) in the kidneys, which increased as the net positive charge per molecule increased to +1 and +2 (∼272 %ID/g and ∼333 %ID/g, respectively), but the -1 and -2 net charged molecules exhibited lower renal uptake (∼15 %ID/g and 16 %ID/g, respectively). Interestingly, the net -2 charged [68Ga]Ga-DOTA-(Glu)2-PEG4-TATE was stable in blood serum but had much higher healthy organ uptake (lungs, liver, spleen) than the net -1 compound, suggesting instability in vivo. Although the [68Ga]Ga-DOTA-PEG4-TATE derivative with a net charge of 0 also showed a decrease in kidney uptake, it also showed instability in blood serum and in vivo. Despite the superior pharmacokinetics of the net -1 charged [68Ga]Ga-DOTA-Glu-PEG4-TATE in healthy mice with respect to kidney uptake and overall profile, dynamic PET images and ex vivo biodistribution in male mice (NSG) bearing AR42J (SSTR2 overexpressing) subcutaneous tumor xenografts showed significantly diminished tumor uptake when compared to the gold standard [68Ga]Ga-DOTA-TATE. Taken together, these findings indicate unambiguously that kidney uptake and retention are significantly influenced by the net charge of peptide-based radiotracers. In addition, it was illustrated that the negatively charged peptides had substantially decreased kidney uptake, but in this instantiation the tumor uptake was also impaired.