Therapeutic radiopharmaceuticals have been researched extensively in the last decade as a result of the growing research interest in personalized medicine to improve diagnostic accuracy and intensify intensive therapy while limiting side effects. Radiometal-based drugs are of substantial interest because of their greater versatility for clinical translation compared to non-metal radionuclides. This paper comprehensively discusses various components commonly used as chemical scaffolds to build radiopharmaceutical agents, i.e., radionuclides, pharmacokinetic-modifying linkers, and chelators, whose characteristics are explained and can be used as a guide for the researcher.

Overexpression of epidermal growth factor receptor (EGFR) is common in colorectal cancer. However, cetuximab as an EGFR‐targeting drug is useful only for a subset of patients and currently no single predictor other than V‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status has been established. In the present study, we investigated cetuximab accumulation in colorectal tumors and major organs using ¹¹¹In‐DOTA‐cetuximab. We also evaluated the potential of positron emission tomography (PET) imaging of ⁶⁴Cu‐DOTA‐cetuximab. Colorectal tumor xenografts with a different EGFR expression level and KRAS mutation status were subjected to in vivo biodistribution study and PET imaging at 48 h post‐injection of radiolabeled cetuximab. The EGFR expression levels on colorectal tumors were determined by ex vivo immunoblotting and ELISA. We found that KRAS wild‐type tumors had significantly higher ¹¹¹In‐DOTA‐cetuximab accumulation than KRAS mutant tumors (P < 0.001). Based on KRAS mutation status, a strong correlation was found between ¹¹¹In‐DOTA‐cetuximab tumor uptake and EGFR expression level (KRAS wild type: r = 0.988; KRAS mutant: r = 0.829), and between ⁶⁴Cu‐DOTA‐cetuximab tumor uptake with EGFR expression level (KRAS wild type: r = 0.838; KRAS mutant: r = 0.927). Significant correlation was also found between tumor uptake of ¹¹¹In‐DOTA‐cetuximab and ⁶⁴Cu‐DOTA‐cetuximab (r = 0.920). PET imaging with ⁶⁴Cu‐DOTA‐cetuximab allowed clear visualization of tumors. Both radiolabeled cetuximab had effectively visualized cetuximab accumulation in colorectal tumors with a wide variety of EGFR expression levels and different KRAS mutation status as commonly encountered in the clinical setting. Our findings suggest that this radioimmunoimaging therefore can be clinically translated as an in vivo tool to predict cetuximab accumulation in colorectal cancer patients prior to cetuximab therapy. (Cancer Sci 2012; 103: 600–605)

The accurate depiction of both biologic and anatomic profiles of tumors has long been a challenge in PET imaging. An inflammation, which is innate in the carcinogenesis of oral squamous cell carcinoma (OSCC), frequently complicates the image analysis because of the limitations of (18)F-FDG and maximum standardized uptake values (SUV(max)). New PET parameters, metabolic tumor volume (MTV) and total lesion glycolysis (TLG), as well as (18)F-fluoro-α-methyltyrosine ((18)F-FAMT), a malignancy-specific amino acid-based PET radiotracer, are considered more comprehensive in tumor image analysis. Here, we showed the substantial effects of the intratumoral inflammatory process on (18)F-FDG uptake and further study the possibility of MTV and TLG to predict both tumor biology (proliferation activity) and anatomy (pathologic tumor volume). (18)F-FDG and (18)F-FAMT PET images from 25 OSCC patients were analyzed. SUV(max) on the tumor site was obtained. PET volume computerized-assisted reporting was used to generate a volume of interest to obtain MTV and TLG for (18)F-FDG and total lesion retention (TLR) for (18)F-FAMT. The whole tumor dissected from surgery was measured and sectioned for pathologic analysis of tumor inflammation grade and Ki-67 labeling index. The high SUV(max) of (18)F-FDG was related to the high inflammation grade. The SUV(max )ratio of (18)F-FDG to (18)F-FAMT was higher in inflammatory tumors (P < 0.05) whereas the corresponding value in tumors with a low inflammation grade was kept low. All (18)F-FAMT parameters were correlated with Ki-67 labeling index (P < 0.01). Pathologic tumor volume predicted from MTV of (18)F-FAMT was more accurate (R = 0.90, bias = 3.4 ± 6.42 cm(3), 95% confidence interval = 0.77-6.09 cm(3)) than that of (18)F-FDG (R = 0.77, bias = 8.1 ± 11.17 cm(3), 95% confidence interval = 3.45-12.67 cm(3)). (18)F-FDG uptake was overestimated by additional uptake related to the intratumoral inflammatory process, whereas (18)F-FAMT simply accumulated in tumors according to tumor activity as evaluated by Ki-67 labeling index in OSCC.

Backgrounds: Overexpression of epidermal growth factor receptor (EGFR) has been established as a valid therapeutic target of non-small cell lung cancer (NSCLC). However, the clinical benefit of cetuximab as an EGFR-targeting drug is still controversial, partially due to the lack of effective means to identify suitable patients. This study aimed to investigate the potential of radiolabeled cetuximab as a non-invasive tool to predict cetuximab accumulation in NSCLC tumor xenografts with varying EGFR expression levels. Methods: The NSCLC tumors in model mice were subjected to in vivo biodistribution study and positron emission tomography (PET) imaging 48 h after injection of either ¹¹¹In- or ⁶⁴Cu-labeled cetuximab. The EGFR expression levels of NSCLC tumors were determined by ex vivo immunoblotting. Results: We found that tumors with high EGFR expression had significantly higher [¹¹¹In]In-DOTA-cetuximab accumulation than tumors with moderate to low EGFR expression (P < 0.05). Strong correlations were found between [¹¹¹In]In-DOTA-cetuximab tumor uptake and EGFR expression level (r = 0.893), and between [⁶⁴Cu]Cu-DOTA-cetuximab tumor uptake with EGFR expression level (r = 0.915). PET imaging with [⁶⁴Cu]Cu-DOTA-cetuximab allowed clear visualization of tumors. Conclusion: Our findings suggest that this immuno-PET imaging can be clinically translated as a tool to predict cetuximab accumulation in NSCLC cancer patients prior to cetuximab therapy.