Radiation dosimetry and fasting-dependent hepatobiliary clearance of the VAChT-specific PET radioligand 18F-VAT in humans.

Background: The vesicular acetylcholine transporter ligand (-)-(1-((2R,3R)-8-(2-[(18)F]fluoro-ethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)(4-fluorophenyl)-methanone (¹⁸F -VAT) enables positron emission tomography PET quantification of cholinergic dysfunction in neurologic and psychiatric disorders. Determining its bio-distribution and dose exposure in humans is essential for clinical implementation, particularly given hepatobiliary clearance observed in pre-clinical models. Based on pre-clinical data, eight healthy subjects (4 males, 4 females) received 385-533 MBq ¹⁸F-VAT immediately followed by three sequential whole-body PET/CT scans. PET data were collected under three different fasting conditions relative to administration of Ensure®Plus oral supplement and PET image acquisition: (1) complete fasting (n = 3), (2) oral partial fasting (n = 3), or (3) non-fasting (n = 2). We defined volumes of interest (VOIs), and generated organ time-activity curves (TACs). Organ radiation dosimetry was calculated using OLINDA/EXM v2.2 software.

Results: There were no adverse events after ¹⁸F-VAT dosing. Radioactivity accumulated predominantly in the brain, hepatobiliary system, small intestine, bone, and urinary bladder. Across all fasting states, organ dosimetry revealed gallbladder as the critical organ (201.0 μSv/MBq) followed by liver (64.3 μSv/MBq), with a gender averaged effective dose of 17.5 ± 2.1 μSv/MBq (15.7 and 19.4 μSv/MBq for males and females, respectively.) Mean gallbladder time integrated activity significantly differed across non-fasting (36.6 MBq*h, 155.5 µSv/MBq), partial fasting (21.8 MBq*h, 107.6 µSv/MBq) and fasting PET acquisition (74.1 MBq*h, 270.5 µSv/MBq) (Kruskal-Wallis H 6.5, p = 0.04).

Conclusions: Human bio-distribution data showed high retention of ¹⁸F-VAT in the gallbladder and liver, where rat dosimetry studies do not accurately predict a safety profile given lack of gallbladder. Human dosimetry data appear different from fasting non-human primate data, indicating that up to 249 MBq (6.7 mCi) of ¹⁸F-VAT can be administered without exceeding a maximum dose to the gallbladder of 50 mSv (5 rem) without consideration of fasting state. Oral supplementation, administered just before and especially 90 min after ¹⁸F-VAT administration, accelerates gallbladder clearance. This reduces critical organ radiation exposure, allowing an administered dose of ¹⁸F-VAT to 465 MBq (12.6 mCi) in the optimal partial fasting state without exceeding a gallbladder dose of 50 mSv (5 rem).