Human biodistribution and radiation dosimetry of the demyelination tracer [18F]3F4AP

Abstract

Purpose [18F]3F4AP is a novel PET radiotracer that targets voltage-gated potassium (K+) channels and has shown promise for imaging demyelinated lesions in animal models of neurological diseases. This study aimed to evaluate the biodistribution, safety, and radiation dosimetry of [18F]3F4AP in healthy human volunteers. Methods Four healthy volunteers (2 females) underwent a 4-h dynamic PET scan from the cranial vertex to mid-thigh using multiple bed positions after administration of 368 ± 17.9 MBq (9.94 ± 0.48 mCi) of [18F]3F4AP. Volumes of interest for relevant organs were manually drawn guided by the CT, and PET images and time-activity curves (TACs) were extracted. Radiation dosimetry was estimated from the integrated TACs using OLINDA software. Safety assessments included measuring vital signs immediately before and after the scan, monitoring for adverse events, and obtaining a comprehensive metabolic panel and electrocardiogram within 30 days before and after the scan. Results [18F]3F4AP distributed throughout the body with the highest levels of activity in the kidneys, urinary bladder, stomach, liver, spleen, and brain and with low accumulation in muscle and fat. The tracer cleared quickly from circulation and from most organs. The clearance of the tracer was noticeably faster than previously reported in nonhuman primates (NHPs). The average effective dose (ED) across all subjects was 12.1 ± 2.2 μSv/MBq, which is lower than the estimated ED from the NHP studies (21.6 ± 0.6 μSv/MBq) as well as the ED of other fluorine-18 radiotracers such as [18F]FDG (~ 20 μSv/MBq). No differences in ED between males and females were observed. No substantial changes in safety assessments or adverse events were recorded. Conclusion The biodistribution and radiation dosimetry of [18F]3F4AP in humans are reported for the first time. The average total ED across four subjects was lower than most 18F-labeled PET tracers. The tracer and study procedures were well tolerated, and no adverse events occurred.

Radiosynthesis automation, non-human primate biodistribution and dosimetry of K+channel tracer [11C]3MeO4AP

“…[ 11 C]3MeO4AP shows low radiation dosimetry based on OLINDA calculation. The effective dose is ∼35 % of [ 18 F]3F4AP (12.2 ± 2.2 μSv/MBq [20], human data) and similar to [ 11 C]choline (4.4 μSv/MBq [21], human data), and [ 11 C]glucose (4.3 μSv/MBq [22], human data). A patient receiving ∼ 400 MBq injection dose of [ 11 C]3MeO4AP will receive ∼ 1.7 mSv of radiation dose from the PET tracer, which is ∼ 1.7 fold of the annual radiation dose limit of individual members of the public (56 FR 23398, May 21, 1991).…”

“…The copyright holder for this preprint this version posted March 28, 2023. ; https://doi.org/10.1101/2023.03.28.534386 doi: bioRxiv preprint [ 11 C]3MeO4AP is notably lower than the fluorine-18 4AP analogue [ 18 F]3F4AP (measured in human: 12.2 ± 2.2 μSv/MBq [20]; measured in NHPs: 21.6 ± 0.6 μSv/MBq [12]) but comparable to the effective dose of other carbon-11 tracers measured in humans (e.g. [ 11 C]choline: 4.4 μSv/MBq [21], [ 11 C]glucose: 4.3 μSv/MBq [22]) .…”

Common anesthetic used in preclinical PET imaging inhibits metabolism of the PET tracer [18F]3F4AP

“…Isoflurane anesthesia results in higher [ 18 F]3F4AP brain uptake Recent studies have shown that [ 18 F]3F4AP uptake is markedly different in anesthetized monkeys 10 and awake human subjects 11 . Analysis of reported PET imaging results shows that at corresponds to an SUV90 min-br(NHP) of 1.50 while human imaging studies in awake subjects show an SUV90 min-br(human) of 0.54.…”

“…Due to its potential for detecting demyelination this tracer has recently advanced into human studies (clinicaltrials.gov: NCT04699747, NCT04710550). First-in-human imaging with [ 18 F]3F4AP revealed widespread biodistribution and high brain penetration, but also exhibited faster than expected clearance rate and greater metabolism of the radiotracer in blood (less than 50% parent remaining 1h post injection) 11 . Given that the metabolic breakdown of the tracer may lead to a reduced brain uptake, introduce background signal, and create variability across subjects, further studies are warranted.…”

Metabolic Stability of the Demyelination Positron Emission Tomography Tracer [18F]3-Fluoro-4-Aminopyridine and Identification of Its Metabolites

“…However, recent findings in humans scanned without anesthesia show that less than 50% parent remains in circulation 1h post intravenous administration (Brugarolas et al 2022) and a study in mice that received [ 18 F]3F4AP awake or under isoflurane showed that non-anesthetized mice readily metabolized the tracer whereas anesthetized animals did not (72±4% vs. 20±5% parent remaining in plasma after 35 min), (Ramos-Torres et al 2022). The observed differences in stability between awake and anesthetized subjects strongly suggest that the high stability in anesthetized animals is mediated by isoflurane.…”