Preparation of molecular probes targeting urokinase plasminogen activator (uPA) for imaging aggressive and metastatic tumors

Objectives A radioimaging probe that selectively targets aggressive and metastatic tumours early in their genesis to aid in determining an appropriate treatment strategy and monitor intervention is needed. Towards this goal, we have designed small molecules that target uPA, a protein known to be a marker for these tumors.

Methods Based on the 2-(4-chloro-7-sulfonamideisoquinolin-1-yl)guanidine core, known to have high specific binding for uPA, we prepared a series of substituted potential imaging agents for evaluation (Figure 1). Eight novel compounds were made in high purity and yield as analyzed by various techniques (NMR,LC-MS,EA). Their binding affinities for uPA were then evaluated via a colorimetric assay. Fluorinated compound 1a was selected for radiolabeling and a protected precursor prepared. Using [¹⁸F]1a and MDA231 cells, cell uptake studies were also performed.

Results Eight new compounds were prepared in high purity and yield. The K_i values varied from nM to µM. Fluoroethyl derivative 1a had a desirable K_i of 58 nM. [¹⁸F]1a was prepared in 22% radiochemical yield and >98% radiochemical purity (70 min). The logP of [¹⁸F]1a was measured to be 0.89 ± 0.03 and the specific cell uptake with MDA 231 cells was determined to be 10.2 % which was blocked using the cold compound.

Conclusions We have prepared and radiolabeled a novel fluorinated compound for PET imaging of uPA expression, a protein known to be overexpressed in aggressive and metastatic tumours.