Use of a Novel Arg-Gly-Asp Radioligand, ¹⁸F-AH111585, to Determine Changes in Tumor Vascularity After Antitumor Therapy

¹ GE Healthcare MDx Research, The Grove Centre, Amersham, United Kingdom
² AstraZeneca, Alderley Park, Macclesfield, Cheshire, United Kingdom
³ GE Healthcare MDx Research, Nycoveien 2, Oslo, Norway

^* To whom correspondence should be addressed. E-mail: matthew.morrison{at}ge.com.

	Abstract

Despite the recent development of various radiolabeled Arg-Gly-Asp (RGD) peptides for imaging the _v3 integrin receptor, relatively little attention has been focused on the ability of these radiotracers to monitor changes in tumor vascularity after antitumor therapies. This study describes the favorable in vivo kinetics and tumor-targeting properties of ¹⁸F-AH111585, a novel ¹⁸F-RGD peptide, and its ability to monitor tumor vascularity noninvasively. Methods: Mice bearing Lewis lung carcinoma (LLC) tumors or Calu-6 non–small cell lung tumor xenografts were used for in vivo biodistribution and small-animal PET imaging studies. In addition, some animals were treated with either low-dose paclitaxel or the vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor ZD4190. Tumor uptake of ¹⁸F-AH111585 and microvessel density were then assessed. Results: Biodistribution of ¹⁸F-AH111585 demonstrated rapid clearance from the blood and key background organs and good tumor accumulation, with 1.5 percentage injected dose per gram (%ID/g) present at 2 h after injection in LLC tumors. Small-animal PET imaging of Calu-6 tumors allowed visualization of tumors above background tissue, with mean baseline uptake of 2.2 %ID/g. Paclitaxel therapy reduced the microvessel density in LLC tumor–bearing mice and resulted in significantly reduced ¹⁸F-AH111585 tumor uptake (P < 0.05). ZD4190 therapy resulted in a significant (31.8%) decrease in ¹⁸F-AH111585 uptake in Calu-6 tumors, compared with the vehicle control–treated Calu-6 tumors, which had a 26.9% increase in ¹⁸F-AH111585 uptake over the same period (P < 0.01). Conclusion: ¹⁸F-AH111585 is a promising ¹⁸F-labeled RGD tracer that offers a new approach to noninvasively image tumor vasculature. This tracer may reveal important information in the assessment of the impact of antitumor therapies, in particular those that predominantly target tumor blood vessels.

Key Words: RGD peptide, PET, integrin _v3, integrin _v5, tumor vasculature, molecular imaging