Hellström-Lindahl Ewa, Åberg Ola, Ericsson Cecilia, O'Mahony Gavin, Johnström Peter, Skrtic Stanko, Eriksson Olof
Division of Molecular Imaging, Department of Medicinal Chemistry, Uppsala University, SE-751 83, Uppsala, Sweden.
AstraZeneca R&D, SE-431 50, Mölndal, Sweden.
Acta Diabetol. 2017 Jul;54(7):663-668. doi: 10.1007/s00592-017-0989-7. Epub 2017 Apr 13.
Molecular imaging of the free fatty acid receptor 1 (FFAR1) would be a valuable tool for drug development by enabling in vivo target engagement studies in human. It has also been suggested as a putative target for beta cell imaging, but the inherent lipophilicity of most FFAR1 binders produces high off-target binding, which has hampered progress in this area. The aim of this study was to generate a suitable lead compound for further PET labeling.
In order to identify a lead compound for future PET labeling for quantitative imaging of FFAR1 in human, we evaluated tritiated small molecule FFAR1 binding probes ([H]AZ1, [H]AZ2 and [H]TAK-875) for their off-target binding, receptor density and affinity in human pancreatic tissue (islets and exocrine) and rodent insulinoma.
[H]AZ1 showed improved specificity to FFAR1, with decreased off-target binding compared to [H]AZ2 and [H]TAK-875, while retaining high affinity in the nanomolar range. FFAR1 density in human islets was approximately 50% higher than in exocrine tissue.
AZ1 is a suitable lead compound for PET labeling for molecular imaging of FFAR1 in humans, due to high affinity and reduced off-target binding.
游离脂肪酸受体1（FFAR1）的分子成像通过实现人体体内靶点结合研究，将成为药物开发的一项有价值工具。它也被认为是β细胞成像的一个潜在靶点，但大多数FFAR1结合剂固有的亲脂性会产生高脱靶结合，这阻碍了该领域的进展。本研究的目的是生成一种适合进一步进行正电子发射断层扫描（PET）标记的先导化合物。
为了确定一种用于未来PET标记以对人体FFAR1进行定量成像的先导化合物，我们评估了氚标记的小分子FFAR1结合探针（[H]AZ1、[H]AZ2和[H]TAK - 875）在人体胰腺组织（胰岛和外分泌组织）以及啮齿动物胰岛素瘤中的脱靶结合、受体密度和亲和力。
与[H]AZ2和[H]TAK - 875相比，[H]AZ1对FFAR1显示出更高的特异性，脱靶结合减少，同时在纳摩尔范围内保持高亲和力。人体胰岛中的FFAR1密度比外分泌组织高约50%。
由于具有高亲和力和减少的脱靶结合，AZ1是用于人体FFAR1分子成像PET标记的合适先导化合物。
