Design, (radio)synthesis and applications of radiolabelled matrix metalloproteinase inhibitors for PET

Dysregulation of matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase (ADAM) activity occurs in a wide range of disease states such as inflammation or cancer. The ability to image MMP/ADAM activity non-invasively in vivo, by radiolabelled synthetic inhibitors, would allow the characterization of inflammatory lesions or tumors. The purpose of this thesis was the design, (radio)synthesis and evaluation of radiolabelled MMP/ADAM inhibitors, mainly for positron emission tomography (PET), in order to profile the levels of MMPs and ADAMs in vivo.
The present dissertation describes the preparation of four novel hydroxamate-based MMP/ADAM inhibitors radiolabelled with fluorine-18, and imaging studies with these PET probes in small animals. First of all, the peptidomimetic inhibitor [18F]FB-ML5 was prepared by direct acylation of the inhibitor ML5 with N-succinimidyl-4-[18F]fluorobenzoate. The novel tracer was evaluated in HT1080 tumor-bearing mice and in a mouse model of pulmonary inflammation. In addition, three piperazine-based MMP/ADAM inhibitors were developed. [18F]-1A and [18F]-2 were synthesized by homoaromatic nucleophilic substitution of their corresponding nitro precursors, whereas [18F]-1B was prepared by click chemistry. These three tracers were evaluated in the HT1080 xenograft mouse model.
All probes exhibited excellent in vitro results (IC50 values for binding to MMP-9, -12 and ADAM-17 ranging from 10-9 to 10-7 M). However, they led to rather disappointing in vivo results. Thus, this dissertation exhibits novel lead structures which should be further optimized to produce suitable PET tracers for MMP/ADAM imaging.