PET-Based Human Dosimetry of the Dimeric α_vβ₃ Integrin Ligand ⁶⁸Ga-DOTA-E-[c(RGDfK)]₂, a Potential Tracer for Imaging Tumor Angiogenesis

Abstract

Peptides containing the Arg-Gly-Asp (RGD) sequence have high affinity for α v β 3 integrin receptors overexpressed in tumor cells. The objective of this research was to determine the biodistribution and estimate the radiation dose from 68 Ga-DOTA-E-[c(RGDfK)] 2 using whole-body PET scans in humans. Methods: Five healthy volunteers (2 women, 3 men; mean age ± SD, 37.2 ± 15.6 y; range, 28-65 y; mean weight, 79.2 ± 21.0 kg; range, 64-115 kg) were included. After intravenous injection of the tracer (198.3 ± 3.3 MBq), 3 successive whole-body (vertex to mid thigh) PET/CT scans at 3 time points (30, 60, and 120 min) were obtained on a 16-slice PET/CT scanner. The subjects did not void the bladder until the entire series of images was completed. Low-dose CT without contrast agent was used for anatomic localization and attenuation correction. OLINDA/ EXM software was applied to calculate human radiation doses using the reference adult model. Results: The highest uptake was in the urinary bladder, followed by the liver, kidneys, and spleen, in descending order. The critical organ was the urinary bladder wall. The mean effective doses (all subjects, men and women) were 34.1 ± 4.9, 31.0 ± 2.4, and 20.9 ± 5.2 μSv/MBq for the no-voiding, 2.5-h-voiding, and 1-h-voiding models, respectively. Conclusion: Of particular interest in this research was the visualization of the choroid plexus and ventricular system, which seems to be a characteristic of RGD-dimeric peptides. Measured absorbed doses and effective doses are comparable to other previously reported RGD-based radiopharmaceuticals labeled with 68 Ga and 18 F. Therefore, 68 Ga-DOTA-E-[c(RGDfK)] 2 can safely be used for imaging integrin α V β 3 expression. The last few years have witnessed the development of a virtual revolution in PET molecular imaging, and radiolabeled receptor-binding peptides are emerging as powerful tools for imaging and therapy applications of tumors expressing peptide binding receptors (1-3). Somatostatin analogs have been in use the longest, have led to the accumulation of a vast amount of data, and have proven useful for the management of patients with neuroendocrine tumors (4-8). Several other peptide receptorbinding compounds have been synthesized within the past few years and are currently in various research stages-in vitro, in vivo, and preclinical studies-but have not yet been approved for clinical use (9-11). These new and rapidly expanding peptide-based radiopharmaceuticals deserve close attention.It has been shown that peptides based on the RGD amino acid sequence have a high affinity and selectivity for a V b 3 integrin receptors (12). The a V b 3 integrins are transmembrane proteins that are preferentially expressed on proliferating endothelial cells but absent from quiescent endothelial cells (13). Integrins are overexpressed on newly formed blood vessels of actively growing tumors and are therefore potential targets for receptor-mediated tumor imaging and therapy when labeled with the proper radionuclide. Angiogenesis, the formation of n...

Response Assessment of 68Ga-DOTA-E-[c(RGDfK)]2 PET/CT in Lung Adenocarcinoma Patients Treated with Nintedanib Plus Docetaxel

“…Additionally, when we assessed PFS, a higher baseline lung tumor volume was associated with a longer period until progression, which was consistent with previous results (16,31,32). Thus, a higher targetable metabolic area might be associated with a higher tumor burden and therefore with a potentially higher treatment efficacy.…”

“…68 Ga-DOTA-E-[c(RGDfK)] 2 was synthesized according to the method described by López-Rodriguez et al (16) PET/CT Interpretation Criteria 2 PET/CT was performed before the start of treatment and again after 2 cycles of treatment. Negative PET/CT results were defined as tracer confined to normal-uptake organs (spleen, urinary bladder, liver) and no other sites with uptake (16,18). Positive results (progressive disease) were defined as at least one focus of abnormally intense uptake, characterized by visual inspection or SUV max measurements.…”

“…In parallel, a v b 3 -targeting radiotracers for the visualization of a v b 3 expression in tumors by PET/ CT have been synthesized, resulting in the use of the generatorproduced radionuclide 68 Ga-DOTA-E-[c(RGDfK)] 2 (10,13). The application of 68 Ga-DOTA-E-[c(RGDfK)] 2 -labeled peptides has attracted interest in cancer imaging because of their physical characteristics along with improved tumor targeting (15,16).…”

68Ga-TRAP-(RGD)3 Hybrid Imaging for the In Vivo Monitoring of αvß3-Integrin Expression as Biomarker of Anti-Angiogenic Therapy Effects in Experimental Breast Cancer

“…α v ß 3 -integrin has recently gained attention as potential imaging target for the non-invasive in vivo characterization of the tumor microenvironment, and first clinical studies investigating radiolabeled RGD compounds in humans have been published [17, 32]. In particular, the in-human use of RGD-based radiotracers proved to be safe with tumor-specific uptake profiles [6, 33].…”

A study of radiogallium aqueous chemistry:in vitroandin vivocharacterisation of67Ga-hydrolysed-stannous fluoride particles

“…Currently the more notable routinely used PET imaging agents are 68 Ga‐DOTATATE, 68 Ga‐DOTANOC and 68 Ga‐DOTATOC for the diagnosis of neuroendocrine tumours, or 68 Ga‐prostate specific membrane antigen (PSMA) for imaging metastatic prostate cancer . There are also other investigational products for imaging the: lungs using 68 Ga‐MAA perfusion agent or 68 Galligas ventilation agent; gastrin‐releasing peptide receptors on cancer cells using 68 Ga‐SB3; over‐expressed integrin activity in lung cancer using 68 Ga‐NOTA‐PRGD2 or integrin αvβ3 expression in other tumour cells with 68 Ga‐DOTA‐E‐[c(RGDfK)] 2 ; and fungal infections using the 68 Ga‐siderophores TAFC or FOXE that are poised for early phase clinical studies . The short 68 min half‐life of 68 Ga, means a radiopharmaceutical containing this isotope is only useful for imaging over a few hours on the same day.…”