Human biodistribution and radiation dosimetry of novel PET probes targeting the deoxyribonucleoside salvage pathway

Journal Article · Fri Dec 03 00:00:00 EST 2010 · European Journal of Nuclear Medicine and Molecular Imaging

DOI:https://doi.org/10.1007/s00259-010-1666-z· OSTI ID:1816632

Schwarzenberg, Johannes ^[1]; Radu, Caius G. ^[2]; Benz, Matthias ^[1]; Fueger, Barbara ^[1]; Tran, Andrew Q. ^[2]; Phelps, Michael E. ^[2]; Witte, Owen N. ^[3]; Satyamurthy, Nagichettiar ^[2]; Czernin, Johannes ^[1]; Schiepers, Christiaan ^[1]

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1. Univ. of California, Los Angeles, CA (United States). David Geffen School of Medicine. Ahmanson Biological Imaging Division. Dept. of Molecular and Medical Pharmacology
2. Univ. of California, Los Angeles, CA (United States). David Geffen School of Medicine. Crump Inst. for Molecular Imaging. Dept. of Molecular and Medical Pharmacology
3. Univ. of California, Los Angeles, CA (United States). David Geffen School of Medicine. Dept. of Microbiology, Immunology, and Molecular Genetics. Howard Hughes Medical Inst.

Purpose: Deoxycytidine kinase (dCK) is a rate-limiting enzyme in deoxyribonucleoside salvage, a metabolic pathway involved in the production and maintenance of a balanced pool of deoxyribonucleoside triphosphates (dNTPs) for DNA synthesis. dCK phosphorylates and therefore activates nucleoside analogs such as cytarabine, gemcitabine, decitabine, cladribine, and clofarabine that are used routinely in cancer therapy. Imaging probes that target dCK might allow stratifying patients into likely responders and nonresponders with dCK-dependent prodrugs. Here we present the biodistribution and radiation dosimetry of three fluorinated dCK substrates, ¹⁸F-FAC, L¹⁸F-FAC, and L¹⁸F-FMAC, developed for positron emission tomography (PET) imaging of dCK activity in vivo. Methods: PET studies were performed in nine healthy human volunteers, three for each probe. After a transmission scan, the radiopharmaceutical was injected intravenously and three sequential emission scans acquired from the base of the skull to mid-thigh. Regions of interest encompassing visible organs were drawn on the first PET scan and copied to the subsequent scans. Activity in target organs was determined and absorbed dose estimated with OLINDA/EXM. The standardized uptake value was calculated for various organs at different times. Results: Renal excretion was common to all three probes. Bone marrow had higher uptake for L¹⁸F-FAC and L¹⁸FFMAC than ¹⁸F-FAC. Prominent liver uptake was seen in L¹⁸F-FMAC and L¹⁸F-FAC, whereas splenic activity was highest for ¹⁸F-FAC. Muscle uptake was also highest for ¹⁸F-FAC. The critical organ was the bladder wall for all three probes. The effective dose was 0.00524, 0.00755, and 0.00910 mSv/MBq for ¹⁸F-FAC, L¹⁸F-FAC, and L¹⁸FFMAC, respectively. Conclusion The biodistribution of ¹⁸F-FAC, L¹⁸F-FAC, and L¹⁸F-FMAC in humans reveals similarities and differences. Differences may be explained by different probe affinities for nucleoside transporters, dCK, and catabolic enzymes such as cytidine deaminase (CDA). Dosimetry demonstrates that all three probes can be used safely to image the deoxyribonucleoside salvage pathway in humans.

• Research Organization: Univ. of California, Los Angeles, CA (United States)
• Sponsoring Organization: USDOE Office of Science (SC); National Institutes of Health (NIH)
• Grant/Contract Number: FG02-06ER64249; P50 CA86306; R24CA92865
• OSTI ID: 1816632
• Journal Information: European Journal of Nuclear Medicine and Molecular Imaging, Vol. 38, Issue 4; ISSN 1619-7070
• Publisher: Springer Nature
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Deoxyribonucleoside salvage pathway
Deoxycytidine kinase
PET imaging
FAC PET
Dosimetry