Biodistribution and radiation dosimetry of the integrin marker 18F-RGD-K5 determined from whole-body PET/CT in monkeys and humans

Abstract

2-((2S,5R,8S,11S)-5-benzyl-8-(4-((2S,3R,4R,5R,6S)-6-((2-(4-(3-(18)F-fluoropropyl)-1H-1,2,3-triazol-1-yl)acetamido)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxamido)butyl)-11-(3-guanidinopropyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaazacyclopentadecan-2-yl)acetic acid ((18)F-RGD-K5) has been developed as an α(v)β(3) integrin marker for PET. The purpose of this study was to determine the biodistribution and estimate the radiation dose from (18)F-RGD-K5 using whole-body PET/CT scans in monkeys and humans.

Methods: Successive whole-body PET/CT scans were obtained after intravenous injection of (18)F-RGD-K5 in 3 rhesus monkeys (167 ± 19 MBq) and 4 healthy humans (583 ± 78 MBq). In humans, blood samples were collected between the PET/CT scans, and stability of (18)F-RGD-K5 was assessed. Urine was also collected between the scans, to determine the total activity excreted in urine. The PET scans were analyzed to determine the radiotracer uptake in different organs. OLINDA/EXM software was used to calculate human radiation doses based on human and monkey biodistributions.

Results: (18)F-RGD-K5 was metabolically stable in human blood up to 90 min after injection, and it cleared rapidly from the blood pool, with a 12-min half-time. For both monkeys and humans, increased (18)F-RGD-K5 uptake was observed in the kidneys, bladder, liver, and gallbladder, with mean standardized uptake values at 1 h after injection for humans being approximately 20, 50, 4, and 10, respectively. For human biodistribution data, the calculated effective dose was 31 ± 1 μSv/MBq, and the urinary bladder wall had the highest absorbed dose at 376 ± 19 μGy/MBq using the 4.8-h bladder-voiding model. With the 1-h voiding model, these doses reduced to 15 ± 1 μSv/MBq for the effective dose and 103 ± 4 μGy/MBq for the absorbed dose in the urinary bladder wall. For a typical injected activity of 555 MBq, the effective dose would be 17.2 ± 0.6 mSv for the 4.8-h model, reducing to 8.3 ± 0.4 mSv for the 1-h model. For monkey biodistribution data, the effective dose to humans would be 22.2 ± 2.4 mSv for the 4.8-h model and 12.8 ± 0.2 mSv for the 1-h model.

Conclusion: The biodistribution profile of (18)F-RGD-K5 in monkeys and humans was similar, with increased uptake in the bladder, liver, and kidneys. There was rapid clearance of (18)F-RGD-K5 through the renal system. The urinary bladder wall received the highest radiation dose and was deemed the critical organ. Both whole-body effective dose and bladder dose can be reduced by more frequent voiding. (18)F-RGD-K5 can be used safely for imaging α(v)β(3) integrin expression in humans.

Trial registration: ClinicalTrials.gov NCT00743353.

Figures

FIGURE 1.

Chemical structure of 18F-RGD-K5

FIGURE 2.

Synthesis of 18F-RGD-K5 from Precursor

FIGURE 3.

Mean percent administered activity and SD for top 3 organs determined on the basis of four 18F- RGD-K5 PET emission scans in human volunteers, as a function of time after injection. Rapid clearance of activity was observed in the organs.

FIGURE 4.

Decay-corrected anterior maximum-intensity projections of PET at 14, 75, 100, 126, 145 minutes (from left to right) after injection of 18F- RGD-K5 in a female volunteer. There was rapid clearance of activity in kidneys, liver and bladder. Gallbladder activity peaked at 75 minutes then decreased with time.

FIGURE 5.

Mean percent administered activity and SD for top 4 organs determined on the basis of 3 rhesus monkey 18F-RGD-K5 PET emission scans, as a function of time after injection. Liver and kidney activities decreased rapidly with time, and bladder activity increased with time (there was no voiding as the monkeys were anesthetized)

FIGURE 6.

Decay-corrected anterior maximum-intensity projections of PET at 1, 13, 43, 112, and 190 minutes (from left to right) after injection of 18F-RGD-K5 in a rhesus monkey. The liver and kidney activities decreased rapidly with time, and bladder and rectum accumulated activity with time (there was no voiding of bladder as the monkey was anesthetized).