Phase I Trial of the Positron-Emitting Arg-Gly-Asp (RGD) Peptide Radioligand ¹⁸F-AH111585 in Breast Cancer Patients

Abstract

The integrin a v b 3 receptor is upregulated on tumor cells and endothelium and plays important roles in angiogenesis and metastasis. Arg-Gly-Asp (RGD) peptide ligands have high affinity for these integrins and can be radiolabeled for PET imaging of angiogenesis or tumor development. We have assessed the safety, stability, and tumor distribution kinetics of a novel radiolabeled RGD-based integrin peptide-polymer conjugate, 18 F-AH111585, and its feasibility to detect tumors in metastatic breast cancer patients using PET. Methods: The biodistribution of 18 F-AH111585 was assessed in 18 tumor lesions from 7 patients with metastatic breast cancer by PET, and the PET data were compared with CT results. The metabolic stability of 18 F-AH111585 was assessed by chromatography of plasma samples. Regions of interest (ROIs) defined over tumor and normal tissues of the PET images were used to determine the kinetics of radioligand binding in tissues. Results: The radiopharmaceutical and PET procedures were well tolerated in all patients. All 18 tumors detected by CT were visible on the 18 F-AH111585 PET images, either as distinct increases in uptake compared with the surrounding normal tissue or, in the case of liver metastases, as regions of deficit uptake because of the high background activity in normal liver tissue. 18 F-AH111585 was either homogeneously distributed in the tumors or appeared within the tumor rim, consistent with the pattern of viable peripheral tumor and central necrosis often seen in association with angiogenesis. Increased uptake compared with background (P 5 0.002) was demonstrated in metastases in lung, pleura, bone, lymph node, and primary tumor. Conclusion: 18 F-AH111585 designed to bind the a v b 3 integrin is safe, metabolically stable, and retained in tumor tissues and detects breast cancer lesions by PET in most anatomic sites.

Integrins as therapeutic targets: lessons and opportunities

“…Given that integrins play important roles in cell attachment, survival, migration, invasion and angiogenesis 17,[51][52][53] , which are all critical for carcinogenesis, they have attracted considerable attention as potential anticancer targets. Usually anti-integrins are used in combination with other anti-cancer agents but they also have potential as imaging agents in cancer diagnosis [54][55] .…”

Monitoring Tumor Response to Antiangiogenic Sunitinib Therapy with 18F-Fluciclatide, an 18F-Labeled αVβ3-Integrin and αVβ5-Integrin Imaging Agent

“…18 F-fluciclatide is currently being developed as a radiotracer for the imaging of angiogenesis in tumors. 18 F-fluciclatide binds with a high affinity to RGD-binding a V b 3 -integrin and a V b 5 -integrin (22), which are upregulated during angiogenesis. Therefore, the uptake of 18 F-fluciclatide can be used to monitor the response of tumors to antiangiogenic drugs, such as sunitinib (Sutent; Pfizer Inc.).…”

Integrin αvβ3 Imaging of Radioactive Iodine–Refractory Thyroid Cancer Using 99mTc-3PRGD2

“…The RGD molecules 99m Tc-NC100692, 18 F-P-PRGD2, 18 F-AH111585, and 18 F-galacto-RGD have already been used in the molecular imaging of cancer cell lines, animal models, or clinical cancer patients (including in murine osteosarcoma, human colon and renal adenocarcinoma, rat pancreatic tumors, ovarian carcinoma, human breast carcinoma, human glioblastoma, and human melanoma) to trace tumor angiogenesis and metastasis with PET or SPECT (8)(9)(10)(11)(12)(13). The integrin a v b 3 expression level on tumor cell membranes correlates well with the RGD radiotracer tumor uptake on scintigraphy imaging (14).…”