Development of ¹⁸F-Labeled Positron Emission Tomography Agents Targeting Fibroblast Activation Protein

Fibroblast activation protein (FAP) is expressed in activated fibroblasts but not in quiescent fibroblasts. Thus, it allows us to use this membrane-anchored enzyme as a target for radionuclide-based tumor diagnosis and treatment and the diagnosis of nonmalignant diseases. In this report, we synthesized and evaluated a series of ¹⁸F-labeled FAP inhibitors (FAPIs), aiming to obtain PET agents with good <i>in vivo</i> distribution and tumor specificity. These ¹⁸F-labeled arene- and aliphatic-vinyl sulfones were prepared with yields of 52.3-78.6%, which were then reacted with FAPIs to obtain corresponding imaging agents with yields of 47.3-88.7% (2nd step). When tested in the U87MG tumor-bearing mice, [¹⁸F]<b>11</b> exhibited 8.2 ± 0.9%ID/g tumor uptake at 0.5 h p.i. with relatively low muscle uptake (T/M ratio of 10.5). In the presence of FAPI inhibitor SP-13786, the tumor uptake of [¹⁸F]<b>11</b> was successfully reduced to 1.4%ID/g, confirming the receptor specificity of this agent. Autoradiography and immunohistochemical staining analysis revealed similar tumor distribution patterns of [¹⁸F]<b>11</b> and FAP⁺ cells in U87MG tumor tissues. Our findings suggest that [¹⁸F]<b>11</b> demonstrates great potential as an FAP-targeted PET agent for tumor detection and can be further evaluated in the future.