Cheung Pierre, Zhang Bo, Puuvuori Emmi, Estrada Sergio, Amin Mohammad A, Ye Sofie, Korsgren Olle, Odell Luke R, Eriksson Jonas, Eriksson Olof
Science for Life Laboratory, Uppsala University, 751 83 Uppsala, Sweden.
Department of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, Sweden.
Biomedicines. 2021 Apr 16;9(4):434. doi: 10.3390/biomedicines9040434.
A validated imaging marker for beta-cell mass would improve understanding of diabetes etiology and enable new strategies in therapy development. We previously identified the membrane-spanning protein GPR44 as highly expressed and specific to the beta cells of the pancreas. The selective GPR44 antagonist MK-7246 was radiolabeled with carbon-11 and the resulting positron-emission tomography (PET) tracer [C]MK-7246 was evaluated in a pig model and in vitro cell lines. The [C]MK-7246 compound demonstrated mainly hepatobiliary excretion with a clearly defined pancreas, no spillover from adjacent tissues, and pancreatic binding similar in magnitude to the previously evaluated GPR44 radioligand [C]AZ12204657. The binding could be blocked by preadministration of nonradioactive MK-7246, indicating a receptor-binding mechanism. [C]MK-7246 showed strong potential as a PET ligand candidate for visualization of beta-cell mass (BCM) and clinical translation of this methodology is ongoing.
一种经过验证的用于评估β细胞量的成像标志物将有助于加深对糖尿病病因的理解，并为开发新的治疗策略提供可能。我们之前发现跨膜蛋白GPR44在胰腺β细胞中高表达且具有特异性。选择性GPR44拮抗剂MK-7246用碳-11进行放射性标记，所得的正电子发射断层扫描（PET）示踪剂[¹¹C]MK-7246在猪模型和体外细胞系中进行了评估。[¹¹C]MK-7246化合物主要通过肝胆途径排泄，胰腺显影清晰，无邻近组织的放射性溢出，胰腺结合程度与之前评估的GPR44放射性配体[¹¹C]AZ12204657相似。预先给予非放射性MK-7246可阻断这种结合，表明其通过受体结合机制发挥作用。[¹¹C]MK-7246作为一种用于可视化β细胞量（BCM）的PET配体候选物显示出强大的潜力，该方法的临床转化正在进行中。
