Preclinical Development and First-in-Human Imaging of the Integrin α v β 6 with [ 18 F]α v β 6 -Binding Peptide in Metastatic Carcinoma.

Purpose: The study was undertaken to develop and evaluate the potential of an integrin alpha(v)beta(6)-binding peptide (alpha(v)beta(6)-BP) for noninvasive imaging of a diverse range of malignancies with PET. Experimental Design: The peptide alpha(v)beta(6)-BP was prepared on solid phase and radiolabeled with 4-[F-18]fluorobenzoic acid. In vitro testing included ELISA, serum stability, and cell binding studies using paired alpha(v)beta(6)-expressing and alpha(v)beta(6)-null cell lines. In vivo evaluation (PET/CT, biodistribution, and autoradiography) was performed in a mouse model bearing the same paired alpha(v)beta(6)-expressing and alpha(v)beta(6)-null cell xenografts. A first-in-human PET/CT imaging study was performed in patients with metastatic lung, colon, breast, or pancreatic cancer. Results: [F-18]alpha(v)beta(6)-BP displayed excellent affinity and selectivity for the integrin alpha(v)beta(6) in vitro [IC50(alpha(v)beta(6)) = 1.2 nmol/L vs IC50(alpha(v)beta(3)) >10 mmol/L] in addition to rapid target-specific cell binding and internalization (72.5% +/- 0.9% binding and 52.5% +/- 1.8%, respectively). Favorable tumor affinity and selectivity were retained in the mouse model and excretion of unbound [F-18]alpha(v)beta(6)-BP was rapid, primarily via the kidneys. In patients, [F-18]alpha(v)beta(6)-BP was well tolerated without noticeable adverse side effects. PET images showed significant uptake of [F-18]alpha(v)beta(6)-BP in both the primary lesion and metastases, including metastasis to brain, bone, liver, and lung. Conclusions: The clinical impact of [F-18]alpha(v)beta(6)-BP PET imaging demonstrated in this first-in-human study is immediate for a broad spectrum of malignancies.