Abstract
1034
Introduction: Matrix metalloproteinases (MMPs) are highly expressed in tumors with metastatic potential, degrading the extracellular matrix to enable metastasis along with mediating tumor growth processes such as angiogenesis. Monitoring their activity via positron emission tomography (PET) would therefore give valuable prognostic information, necessitating the development of effective novel MMP-targeting PET radiotracers. Previous work showed MMP-expressing tumors in mice could be visualized via PET using marimastat, a broad-spectrum MMP inhibitor, possessing a [18F]aryltrifluoroborate group; however, the image suffered from low tumor uptake and poor contrast. We hypothesized that marimastat carrying a hydrophilic DOTA group chelated with high specific activity [68Ga]Ga+3 would improve image quality. Materials and Methods: The marimastat radiotracer was synthesized with a terminal free amine, per literature procedures, which was conjugated with DOTA-NHS-ester. The radiotracer was prepared by incubating DOTA-marimastat with [68Ga]GaCl3 in acetate buffer with microwave heating and was purified via HPLC. [68Ga]Ga-DOTA-marimastat was injected intravenously to A673 tumor-bearing mice. PET imaging and biodistribution studies were performed at 1h post-injection, with blocking studies performed with co-injection of marimastat.
Results: [68Ga]Ga-DOTA-marimastat was synthesized with an average decay-corrected radiochemical yield of 76.5% (n=2), >99% radiochemical purity and an average specific activity of 46.3 GBq/μmol. PET imaging of A673 tumor-bearing mice at 1 h post-injection enabled visualization of the tumor with markedly improved contrast. Biodistribution studies showed radioactivity uptake of 1.2 %ID/g in A673 tumor xenografts versus 0.45 and 0.11 %ID/g in blood and muscle respectively at 1h post-injection. Blocking studies demonstrated a reduction of tumour uptake by 40%. A dynamic scan showed rapid renal excretion at 5 minutes post-injection.
Conclusions: We have developed a radiotracer that images tumoral MMP activity but excretes too rapidly for effective tumor accumulation. Future work will be focused on slowing down excretion to improve imaging capabilities.