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

Abstract

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, (18)F-FAC, L: -(18)F-FAC, and L: -(18)F-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 L: -(18)F-FAC and L: -(18)F-FMAC than (18)F-FAC. Prominent liver uptake was seen in L: -(18)F-FMAC and L: -(18)F-FAC, whereas splenic activity was highest for (18)F-FAC. Muscle uptake was also highest for (18)F-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 (18)F-FAC, L: -(18)F-FAC, and L: -(18)F-FMAC, respectively.

Conclusion: The biodistribution of (18)F-FAC, L: -(18)F-FAC, and L: -(18)F-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.

Fig. 1

a The dCK-dependent nucleoside analog prodrug gemcitabine (dFdC) and ¹⁸F-FAC analogs share a common transport (ENT1) and phosphorylation (dCK) mechanism. Both gemcitabine and ¹⁸F-FAC are subject to deamination by cytidine deaminase (CDA). 5′-NT 5′-nucleotidase, MP monophosphate, TP triphosphate. b FDA-approved drugs that require dCK for their pharmacodynamic effects and the time line of their approval. Note the diversity of the chemical structures of these drugs, indicating the ability of dCK to phosphorylate both pyrimidine and purine analogs

Fig. 2

Projection images obtained in three healthy volunteers using different FAC analogs. Organs are indicated by arrows (B bone marrow, Bl bladder, K kidney, L liver, M myocardium, S spleen, SG salivary gland). Note the high splenic uptake for ¹⁸F-FAC while hepatic uptake was highest for L-¹⁸F-FAC and L-¹⁸F-FMAC. Bone marrow was visualized with all three tracers; marked tracer clearance is seen from kidneys into the bladder. The images are scaled to the maximum liver uptake, i.e., SUV 1.7 for the left panel, SUV 6.8 for the middle panel, and SUV 4.9 for the right panel; this permits direct comparison

Fig. 3

Dynamic changes in probe uptake; average of three volunteers per probe. Uptake is expressed as standardized uptake value (SUV_mean). ¹⁸F-FAC activity in liver and spleen decreased over time while liver uptake of L-¹⁸F-FAC and L-¹⁸F-FMAC increased slightly. Bone marrow uptake was lowest for ¹⁸F-FAC. Uptake is also noted in salivary glands and muscles (most prominently for ¹⁸F-FAC)

Fig. 4

¹⁸F-FAC images obtained in a patient with diffuse large B-cell lymphoma. The CT scan (left panel) shows extensive left axillary lymphadenopathy (arrow). This corresponds to a region of increased tracer uptake on the PET images suggesting that dCK expression of this lesion is high. B bone marrow, Bl bladder, K kidney, L liver, LA lymphadenopathy, M myocardium, S spleen. The scan was started 30 min after administration of 300 MBq of ¹⁸F-FAC. See Table 3 for effective dose estimates

Fig. 5

Selected axial slices of PET/CT fusion (a), CT (b), and PET (c) obtained in a patient with metastatic ovarian cancer, demonstrating L-¹⁸F-FMAC uptake in a metastatic lesion located in the gastric antrum. On PET/CT fusion images (a) physiologic uptake of L-¹⁸F-FMAC is seen in the liver (yellow arrow) and pancreas (blue arrow); excreted L-¹⁸F-FMAC is seen in both kidneys (white arrows). Incidental note is made of a large right renal cyst (white arrowhead). The scan was started 26 min after administration of 344 MBq of the radiopharmaceutical. Table 3 provides absorbed dose estimates