Science for Life Laboratory, Department of Medicinal Chemistry, Uppsala University, Dag Hammarskjöldsv 14C, 3rd floor, 75183, Uppsala, Sweden.
Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
Sci Rep. 2021 Dec 28;11(1):24466. doi: 10.1038/s41598-021-04188-6.
Biomarkers for the measurement of islets of Langerhans could help elucidate the etiology of diabetes. Synaptic vesicle glycoprotein 2 A (SV2A) is a potential marker reported to be localized in the endocrine pancreas. [C]UCB-J is a novel positron emission tomography (PET) radiotracer that binds to SV2A and was previously evaluated as a synaptic marker in the central nervous system. Here, we evaluated whether [C]UCB-J could be utilized as a PET tracer for the islets of Langerhans in the pancreas by targeting SV2A. The mRNA transcription of SV2A was evaluated in human isolated islets of Langerhans and exocrine tissue. In vitro autoradiography was performed on pancreas and brain sections from rats and pigs, and consecutive sections were immunostained for insulin. Sprague-Dawley rats were examined with PET-MRI and ex vivo autoradiography at baseline and with administration of levetiracetam (LEV). Similarly, pigs were examined with dynamic PET-CT over the pancreas and brain after administration of [C]UCB-J at baseline and after pretreatment with LEV. In vivo radioligand binding was assessed using a one-compartment tissue model. The mRNA expression of SV2A was nearly 7 times higher in endocrine tissue than in exocrine tissue (p < 0.01). In vitro autoradiography displayed focal binding of [C]UCB-J in the pancreas of rats and pigs, but the binding pattern did not overlap with the insulin-positive areas or with ex vivo autoradiography. In rats, pancreas binding was higher than that in negative control tissues but could not be blocked by LEV. In pigs, the pancreas and brain exhibited accumulation of [C]UCB-J above the negative control tissue spleen. While brain binding could be blocked by pretreatment with LEV, a similar effect was not observed in the pancreas. Transcription data indicate SV2A to be a valid target for imaging islets of Langerhans, but [C]UCB-J does not appear to have sufficient sensitivity for this application.
用于测量胰岛的生物标志物有助于阐明糖尿病的病因。突触小泡糖蛋白 2A（SV2A）是一种潜在的标志物，据报道其定位于内分泌胰腺。[C]UCB-J 是一种新型正电子发射断层扫描（PET）示踪剂，与 SV2A 结合，之前已在中枢神经系统中作为突触标志物进行了评估。在这里，我们通过靶向 SV2A 来评估 [C]UCB-J 是否可用作胰腺中胰岛的 PET 示踪剂。评估了 SV2A 的 mRNA 转录在人胰岛和外分泌组织中的表达。在大鼠和猪的胰腺和脑组织切片上进行体外放射自显影，并对胰岛素进行连续切片免疫染色。使用 PET-MRI 和基础状态下的外显子放射性自显影以及给予左乙拉西坦（LEV）后对 Sprague-Dawley 大鼠进行检查。同样，在给予 LEV 预处理后，使用动态 PET-CT 在基线和胰腺及脑部后检查猪。使用单室组织模型评估体内放射性配体结合。内分泌组织中 SV2A 的 mRNA 表达比外分泌组织高近 7 倍（p<0.01）。体外放射自显影显示 [C]UCB-J 在大鼠和猪的胰腺中呈局灶性结合，但结合模式与胰岛素阳性区域或离体放射性自显影不重叠。在大鼠中，胰腺结合高于阴性对照组织，但不能被 LEV 阻断。在猪中，胰腺和大脑中 [C]UCB-J 的积累高于阴性对照组织脾脏。虽然脑结合可以通过 LEV 预处理阻断，但在胰腺中未观察到类似的效果。转录数据表明 SV2A 是成像胰岛的有效靶点，但 [C]UCB-J 似乎不具备足够的灵敏度用于该应用。
