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Background <p>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 (<sup>18</sup>F -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&#xa0;MBq <sup>18</sup>F-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.</p> Results <p>There were no adverse events after <sup>18</sup>F-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&#xa0;MBq*h, 155.5 µSv/MBq), partial fasting (21.8&#xa0;MBq*h, 107.6 µSv/MBq) and fasting PET acquisition (74.1&#xa0;MBq*h, 270.5 µSv/MBq) (Kruskal–Wallis H 6.5, p = 0.04).</p> Conclusions <p>Human bio-distribution data showed high retention of <sup>18</sup>F-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&#xa0;MBq (6.7&#xa0;mCi) of <sup>18</sup>F-VAT can be administered without exceeding a maximum dose to the gallbladder of 50&#xa0;mSv (5&#xa0;rem) without consideration of fasting state. Oral supplementation, administered just before and especially 90&#xa0;min after <sup>18</sup>F-VAT administration, accelerates gallbladder clearance. This reduces critical organ radiation exposure, allowing an administered dose of <sup>18</sup>F-VAT to 465&#xa0;MBq (12.6&#xa0;mCi) in the optimal partial fasting state without exceeding a gallbladder dose of 50&#xa0;mSv (5&#xa0;rem).</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月7日

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  • Scott A. Norris,
  • Noah L. Goldman,
  • Mahdjoub Hamdi,
  • Stephen M. Moerlein,
  • Richard Laforest,
  • Morvarid Karimi,
  • Joel S. Perlmutter,
  • Zhude Tu

摘要

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).