Dataset Information

Improved in vivo PET imaging of the adenosine A_2A receptor in the brain using [¹⁸F]FLUDA, a deuterated radiotracer with high metabolic stability.

ABSTRACT:

Purpose

The adenosine A_2A receptor has emerged as a therapeutic target for multiple diseases, and thus the non-invasive imaging of the expression or occupancy of the A_2A receptor has potential to contribute to diagnosis and drug development. We aimed at the development of a metabolically stable A_2A receptor radiotracer and report herein the preclinical evaluation of [¹⁸F]FLUDA, a deuterated isotopologue of [¹⁸F]FESCH.

Methods

[¹⁸F]FLUDA was synthesized by a two-step one-pot approach and evaluated in vitro by autoradiographic studies as well as in vivo by metabolism and dynamic PET/MRI studies in mice and piglets under baseline and blocking conditions. A single-dose toxicity study was performed in rats.

Results

[¹⁸F]FLUDA was obtained with a radiochemical yield of 19% and molar activities of 72-180 GBq/μmol. Autoradiography proved A_2A receptor-specific accumulation of [¹⁸F]FLUDA in the striatum of a mouse and pig brain. In vivo evaluation in mice revealed improved stability of [¹⁸F]FLUDA compared to that of [¹⁸F]FESCH, resulting in the absence of brain-penetrant radiometabolites. Furthermore, the radiometabolites detected in piglets are expected to have a low tendency for brain penetration. PET/MRI studies confirmed high specific binding of [¹⁸F]FLUDA towards striatal A_2A receptor with a maximum specific-to-non-specific binding ratio in mice of 8.3. The toxicity study revealed no adverse effects of FLUDA up to 30 μg/kg, ~ 4000-fold the dose applied in human PET studies using [¹⁸F]FLUDA.

Conclusions

The new radiotracer [¹⁸F]FLUDA is suitable to detect the availability of the A_2A receptor in the brain with high target specificity. It is regarded ready for human application.

SUBMITTER: Lai TH

PROVIDER: S-EPMC8263428 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Publications

Improved in vivo PET imaging of the adenosine A<sub>2A</sub> receptor in the brain using [<sup>18</sup>F]FLUDA, a deuterated radiotracer with high metabolic stability.

Lai Thu Hang TH Toussaint Magali M Teodoro Rodrigo R Dukić-Stefanović Sladjana S Gündel Daniel D Ludwig Friedrich-Alexander FA Wenzel Barbara B Schröder Susann S Sattler Bernhard B Moldovan Rareş-Petru RP Falkenburger Björn H BH Sabri Osama O Deuther-Conrad Winnie W Brust Peter P

European journal of nuclear medicine and molecular imaging 20210202 9

<h4>Purpose</h4>The adenosine A<sub>2A</sub> receptor has emerged as a therapeutic target for multiple diseases, and thus the non-invasive imaging of the expression or occupancy of the A<sub>2A</sub> receptor has potential to contribute to diagnosis and drug development. We aimed at the development of a metabolically stable A<sub>2A</sub> receptor radiotracer and report herein the preclinical evaluation of [<sup>18</sup>F]FLUDA, a deuterated isotopologue of [<sup>18</sup>F]FESCH.<h4>Methods</h4> ...[more]

PMID: 33532910

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Project description:18F-T807 is a PET radiotracer developed for imaging tau protein aggregates, which are implicated in neurologic disorders including Alzheimer disease and traumatic brain injury (TBI). The current study characterizes 18F-T807 pharmacokinetics in human subjects using dynamic PET imaging and metabolite-corrected arterial input functions. Methods: Nine subjects (4 controls, 3 with a history of TBI, 2 with mild cognitive impairment due to suspected Alzheimer disease) underwent dynamic PET imaging for up to 120 min after bolus injection of 18F-T807 with arterial blood sampling. Total volume of distribution (VT) was estimated using compartmental modeling (1- and 2-tissue configurations) and graphical analysis techniques (Logan and multilinear analysis 1 [MA1] regression methods). Reference region-based methods of quantification were explored including Logan distribution volume ratio (DVR) and static SUV ratio (SUVR) using the cerebellum as a reference tissue. Results: The percentage of unmetabolized 18F-T807 in plasma followed a single exponential with a half-life of 17.0 ± 4.2 min. Metabolite-corrected plasma radioactivity concentration fit a biexponential (half-lives, 18.1 ± 5.8 and 2.4 ± 0.5 min). 18F-T807 in gray matter peaked quickly (SUV > 2 at ∼5 min). Compartmental modeling resulted in good fits, and the 2-tissue model with estimated blood volume correction (2Tv) performed best, particularly in regions with elevated binding. VT was greater in mild cognitive impairment subjects than controls in the occipital, parietal, and temporal cortices as well as the posterior cingulate gyrus, precuneus, and mesial temporal cortex. High focal uptake was found in the posterior corpus callosum of a TBI subject. Plots from Logan and MA1 graphical methods became linear by 30 min, yielding regional estimates of VT in excellent agreement with compartmental analysis and providing high-quality parametric maps when applied in voxelwise fashion. Reference region-based approaches including Logan DVR (t* = 55 min) and SUVR (80- to 100-min interval) were highly correlated with DVR estimated using 2Tv (R2 = 0.97, P < 0.0001). Conclusion:18F-T807 showed rapid clearance from plasma and properties suitable for tau quantification with PET. Furthermore, simplified approaches using DVR (t* = 55 min) and static SUVR (80-100 min) with cerebellar reference tissue were found to correlate highly with compartmental modeling outcomes.

Dataset Information

Improved in vivo PET imaging of the adenosine A_2A receptor in the brain using [¹⁸F]FLUDA, a deuterated radiotracer with high metabolic stability.

Purpose

Methods

Results

Conclusions

Publications

Improved in vivo PET imaging of the adenosine A<sub>2A</sub> receptor in the brain using [<sup>18</sup>F]FLUDA, a deuterated radiotracer with high metabolic stability.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Improved in vivo PET imaging of the adenosine A2A receptor in the brain using [18F]FLUDA, a deuterated radiotracer with high metabolic stability.

Purpose

Methods

Results

Conclusions

Publications

Improved in vivo PET imaging of the adenosine A<sub>2A</sub> receptor in the brain using [<sup>18</sup>F]FLUDA, a deuterated radiotracer with high metabolic stability.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Improved in vivo PET imaging of the adenosine A_2A receptor in the brain using [¹⁸F]FLUDA, a deuterated radiotracer with high metabolic stability.