Patient management in oncology increasingly relies upon imaging for diagnosis, response assessment, and follow-up. The clinical availability of combined functional-anatomic imaging modalities, which integrate the benefits of visualizing tumor biology with those of high-resolution structural imaging, revolutionized clinical management of oncologic patients.[1–6] Conventional high resolution anatomic imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) excel at providing details regarding lesion location, size, morphology, and structural changes to adjacent tissues; however, these modalities provide little insight into tumor physiology. With the increasing focus on molecularly targeted therapies, imaging radiolabeled compounds with positron emission tomography (PET) and single photon emission tomography (SPECT) are often used to provide insight into a tumor's biologic functions and its surrounding microenvironment. Despite their high sensitivity and specificity, PET and SPECT alone are substantially limited by low spatial resolution and inability to provide anatomic detail. Integrating SPECT or PET with a modality capable of providing these (i.e. CT or MR) maximizes their separate strengths and provides anatomic localization of physiologic processes with detailed visualization of a tumor's structure. The availability of multi-modality (hybrid) imaging with PET/CT, SPECT/CT and PET/MR improves our ability to characterize lesions and to affect treatment decisions and patient management. We have just begun to exploit the truly synergistic capabilities of multi-modality imaging. Continued advances in instrumentation and imaging agent development will improve our ability to noninvasively characterize disease processes. This review will discuss the evolution of hybrid imaging technology and provide examples of its current and potential future clinical uses.

The over-expression and -activation of hepatocyte growth factor receptor (Met) in various cancers has been linked to increased proliferation, progression to metastatic disease, and drug resistance. Developing a PET imaging agent to assess Met expression would aid in diagnosis and monitoring responses to Met-targeted therapies. In these studies Onartuzumab (MetMAb), the experimental therapeutic one-armed monoclonal antibody, was radiolabeled with 76Br or 89Zr and evaluated as an imaging agent in Met expressing cell lines and mouse xenografts. Methods 89Zr-df-Onartuzumab was synthesized using a desferrioxamine-Onartuzumab conjugate (df-Onartuzumab); 76Br-Onartuzumab was labeled directly. Met binding studies were performed using the human tumor-derived cell lines MKN-45, SNU-16 and U87-MG, which have relatively high, moderate and low levels of Met, respectively. Biodistribution and microPET imaging studies were performed in MKN-45 and U87-MG xenografts. Results 76Br-Onartuzumab and 89Zr-df-Onartuzumab exhibited specific, high affinity Met binding (nM) that was concordant with established Met expression levels. In MKN-45 (gastric carcinoma) xenografts, both tracers cleared slowly from non-target tissues with the highest uptakes in tumor, blood, kidney, and lung. 76Br-Onartuzumab MKN-45 tumor uptakes remained relatively constant from 18 h (5%ID/g) to 48 h (3%ID/g) and exhibited tumor:muscle ratios ranging from 4:1 to 6:1. In contrast, 89Zr-df-Onartuzumab MKN-45 tumor uptake continued to accumulate from 18 h (10%ID/g) to 120 h (23%ID/g), attaining tumor:muscle ratios ranging from 20:1 to 27:1. MKN-45 tumors were easily visualized in imaging studies with both tracers at 18 h but after 48 h 89Zr-df-Onartuzumab image quality improved with at least 2 fold greater tumor uptakes compared to non-target tissues. MKN-45 tumor uptakes for both tracers correlated significantly with tumor mass and Met expression, and were not affected by the presence of plasma shed Met. Conclusions 89Zr-df-Onartuzumab and 76Br-Onartuzumab specifically targeted Met in vitro and in vivo; 89Zr-df-Onartuzumab achieved higher tumor uptakes and tumor:muscle ratios than 76Br-Onartuzumab at later times suggesting that 89Zr-df-Onartuzumab would be better suited to image Met for diagnostic and prognostic purposes.