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

Abstract

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).

Keywords: PET; Radiation dosimetry; VAChT; Vesicular acetylcholine transporter.

Fig. 1

Timeline of study day events around PET data acquisition

Fig. 2

Participant #6 maximum intensity coronal projection (MIP) of all PET frames in the A first, B second, and C third PET segments with decay-corrected standard uptake values (SUV) demonstrating high uptake in the muscle, liver, gallbladder, small intestine, urinary bladder, as well as brain

Fig. 3

Non-decay-corrected organ time-activity curves for participant 6. %ID = percentage injected dose

Fig. 4

Non-decay corrected gallbladder TACS for individual participants. Red text describes fasting versus non-fasting states, where the time of oral supplementation is indicated relative to PET data acquisition. Note trends of increasing TAC across PET segments in the fasting state (participants 1,5,6), reduction in TAC following oral supplementation when administered between PET segments 1&2 (participants 3,7) and reduced overall TAC when oral supplementation is administered prior to PET acquisition (participants 4 and 8). Participant #2 was intended to fast but had a small mean 2 h prior to PET acquisition