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J Nucl Med. 2018 Nov 2. pii: jnumed.118.216994. doi: 10.2967/jnumed.118.216994. [Epub ahead of print]

Biodistribution, tumor detection and radiation dosimetry of F-18 5-Fluoro-2'-Deoxycytidine (18F-FdCyd) with Tetrahydrouridine in solid tumors.

Author information

1
Department of Radiology, Walter Reed National Military Medical Center, United States.
2
Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., United States.
3
Cancer Imaging Program, National Cancer Institute, National Institutes of Health, United States.
4
Molecular Imaging Program, National Cancer Institute, National Institutes of Health, United States.
5
Developmental Therapeutics Program, National Cancer Institute, National Institutes of Health, United States.
6
Stanford University School of Medicine, United States.

Abstract

In pre-clinical studies, 5-fluoro-2'-deoxycytidine (FdCyd), an inhibitor of DNA methyltransferase and DNA hypermethylation, has shown treatment efficacy against multiple malignancies by suppressing epigenetic hypermethylation in tumor cells. Several clinical trials are undergoing using FdCyd and while some patients may respond to this drug, in the majority of patients it is ineffective. Thus, by establishing a non-invasive imaging modality to evaluate the distribution of the drug may provide insight into the variable responses. Objective: A novel experimental radiopharmaceutical, Fluorine-18 labeled FdCyd (18F-FdCyd), was developed as a companion imaging agent to the non-radioactive form of the drug, FdCyd. We present the first-in human radiation dosimetry results and biodistribution of 18F-FdCyd, administered along with tetrahydrouridine, an inhibitor of cytidine/deoxycytidine deaminase, in patients with a variety of solid tumors undergoing FdCyd therapy. Methods: This phase 0 imaging trial examined the 18F-FdCyd biodistribution and radiation dosimetry in 5 human subjects enrolled in companion therapy trials. In each subject, four sequential PET scans were acquired to estimate whole body and individual organ effective dose, using OLINDA/EXM v1.0. Tumor to background (T:B) ratios were also calculated for the tumor sites visualized on PET/CT imaging. Results: Average whole body effective dose for the experimental radiopharmaceutical 18F-FdCyd administered in conjunction with tetrahydrouridine was 2.12E-02 ± 4.15E-03 mSv/MBq. This is similar to the radiation dose estimates for 18F-FDG PET. The critical organ, with the highest absorbed radiation dose was the urinary bladder wall at 7.96E-02 mSv/MBq. Other organ doses of note were the liver (6.02E-02mSv/MBq), kidneys (5.26E-02 mSv/MBq), and gallbladder (4.05E-02 mSv/MBq). Tumor target to background ratios ranged from 2.4 to 1.4, which potentially enable tumor visualization in static PET images. Conclusion: This phase 0 imaging clinical trial provides evidence that 18F-FdCyd administered in conjunction with tetrahydrouridine yields acceptable individual organ and whole body effective doses, as well as modest T:B ratios that potentially enable tumor visualization. Dose estimates for 18F-FdCyd are comparable to those of other PET radiopharmaceuticals such as 18F-FDG. Further studies with larger study population are warranted to assess 18F-FdCyd imaging as a predictor of FdCyd treatment effectiveness.

KEYWORDS:

18F-FdCyd; Cancer; Molecular Imaging; Oncology: General; PET imaging; PET/CT; Radiobiology/Dosimetry; Radiopharmaceuticals; Tetrahydrouridine

PMID:
30389817
DOI:
10.2967/jnumed.118.216994

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