Molecular imaging is the visual representation of biological processes that take place at the cellular or molecular level in living organisms. To date, molecular imaging plays an important role in the transition from conventional medical practice to precision medicine. Among all imaging modalities, positron emission tomography (PET) has great advantages in sensitivity and the ability to obtain absolute imaging quantification after corrections for photon attenuation and scattering. Due to the ability to label a host of unique molecules of biological interest, including endogenous, naturally occurring substrates and drug-like compounds, the role of PET has been well established in the field of molecular imaging. In this article, we provide an overview of the recent advances in the development of PET radiopharmaceuticals and their clinical applications in oncology.

Purpose: Because surgery is the only potential cure for pancreatic cancer, high-risk premalignant pancreatic lesions often evade detection by palpation or white-light visualization, increasing the risk of recurrence. We asked whether near-infrared fluorescence imaging of tumor-associated inflammation could identify high-risk premalignant lesions, leveraging the tumor microenvironment as a sentinel of local disease and, thus, enhance surgery outcomes. Experimental Design: Fluorescence-guided surgery was performed on genetically engineered mice [Ptf1a-Cre; LSL-KrasG12D/+; Smad4flox/flox (KSC)] at discrete stages of disease progression, histologically confirmed high-risk, premalignant lesions in postnatal mice to locally advanced pancreatic tumors in adults, using the imaging agent V-1520, a translocator protein ligand. Age-matched wild-type littermates were used as controls, whereas Ptf1a-Cre; LSL-KrasG12D/+ mice modeled pancreatitis and precursors of low penetrance. Localization of V-1520 and tumor-associated macrophages among the tumor microenvironment was detected by immunofluorescence imaging. Results: V-1520 exhibited robust accumulation in the pancreata of KSC mice from the early postnatal stage. Increased accumulation was observed in the pancreata of adolescent- and adult-aged mice with greater ductal lesion and stromal burden. Confocal microscopy of ex vivo pancreas specimens co-localized V-1520 accumulation primarily with CD68-expressing macrophages in KSC mice. Unlike the pancreata of KSC mice, accumulation of V-1520 did not exceed background levels in the pancreata of Ptf1a-Cre; LSL-KrasG12D/+ mice with pancreatitis. Conclusions: V-1520 exhibited differential accumulation in pancreatic cancer–associated inflammation compared with pancreatitis. Given the robust tracer uptake in tissues associated with early yet high-risk lesions, we envision that V-1520 could enhance surgical resection and reduce the potential for recurrence from residual disease.

Purpose: The high mortality associated with metastatic colorectal cancer (mCRC) illuminates an unmet need for innovative therapeutic modalities. Radiopharmaceutical therapy (RPT) offers a potent, molecular-scale approach for managing and treating cancers with distant micrometastases. However, its clinical use in mCRC remains an unrealized opportunity. We have therefore identified the transmembrane glycoprotein mucin 13 (MUC13) as a promising antigen for developing a targeted RPT and have undertaken preclinical evaluation of its potential by utilizing a monoclonal antibody tool representative of a future class of translatable therapeutics. Experimental Design: The immunoreactivity and transcriptome of patients with colorectal cancer (n = 72 primary, 100 liver metastases) were characterized using annotated clinical datasets. Preclinical assessment of MUC13 as an RPT target for mCRC was then performed in mice using a monoclonal MUC13-targeted antibody C14 labeled with either zirconium-89 for positron emission tomography (PET) measurement of mCRC-associated MUC13 density or terbium-161 for targeted RPT. Results: Strong MUC13 immunoreactivity was observed in ∼70% of mCRC and was inversely correlated with overall survival (P < 0.01). MUC13 levels were visualized by PET and agreed with immunohistochemically determined antigen presence. Furthermore, MUC13-targeted RPT exhibited in vivo proof-of-concept efficacy and enhanced survival in preclinical colorectal cancer models. Resulting imaging, therapeutic, and pathologic analyses elucidated relationships between target density, therapeutic outcome, and a potential genetic signature. Conclusions: MUC13-targeted RPT response was not only associated with radiopharmaceutical accumulation but also seemed to be balanced by DNA damage repair gene expression, suggesting a potential sensitivity signature that could complement a future clinical theranostic approach in MUC13-positive mCRC.

Supplementary Figure S3. Representative chromatograms of purified 161Tb-labeled immunoconjugates. Radio-thin layer chromatograms (A) and radio-size-exclusion chromatograms (B) of [161Tb]Tb-DOTA-C14 and [161Tb]Tb-DOTA-IgG.

Supplementary Figure S5. Survival benefit and health status of CDX-bearing mice in multidose 161Tb radiopharmaceutical therapy study. Probability of survival (A, B) and effect of 161Tb-labeled antibody administration on body weight as an indicator of overall health (C, D) in T84 tumor-bearing (A, C) and SNU-C4 tumor-bearing (B, D) mice. Statistical significance in survival data calculated by Log-rank test. Body weight data are presented as mean±SD. No significant body weight loss caused by either treatment was observed over the course of study.