Characterization in Humans of ¹⁸F-MNI-444, a PET Radiotracer for Brain Adenosine 2A Receptors

Abstract

PET with selective adenosine 2A receptor (A 2A ) radiotracers can be used to study a variety of neurodegenerative and neuropsychiatric disorders in vivo and to support drug-discovery studies targeting A 2A . The aim of this study was to describe the first in vivo evaluation of 18 F-MNI-444, a novel PET radiotracer for imaging A 2A , in healthy human subjects. Methods: Ten healthy human volunteers were enrolled in this study; 6 completed the brain PET studies and 4 participated in the whole-body PET studies. Arterial blood was collected for invasive kinetic modeling of the brain PET data. Noninvasive methods of data quantification were also explored. Test-retest reproducibility was evaluated in 5 subjects. Radiotracer distribution and dosimetry was determined using serial whole-body PET images acquired over 6 h post-radiotracer injection. Urine samples were collected to calculate urinary excretion. Results: After intravenous bolus injection, 18 F-MNI-444 rapidly entered the brain and displayed a distribution consistent with known A 2A densities in the brain. Binding potentials ranging from 2.6 to 4.9 were measured in A 2A -rich regions, with an average test-retest variability of less than 10%. The estimated whole-body radiation effective dose was approximately 0.023 mSv/MBq. Conclusion: 18 F-MNI-444 is a useful PET radiotracer for imaging A 2A in the human brain. The superior in vivo brain kinetic properties of 18 F-MNI-444, compared with previously developed A 2A radiotracers, provide the opportunity to foster global use of in vivo A 2A PET imaging in neuroscience research.

Preclinical Evaluation and Quantification of 18F-Fluoroethyl and 18F-Fluoropropyl Analogs of SCH442416 as Radioligands for PET Imaging of the Adenosine A2A Receptor in Rat Brain

“…However, for translation into a clinical setting, the presented metabolite results and optimal compartmental models need to be reevaluated for 18 F-FESCH brain uptake in humans, because of possible interspecies differences in tracer kinetics and metabolism. Because the cerebellum demonstrated low to negligible A 2A receptor density in autoradiography experiments with human brain tissue (35), previous studies with A 2A receptor-specific radiotracers in humans have used cerebellum as a reference region (16). This reference tissue approach could also be considered for the quantification of 18 F-FESCH in a clinical setting, thus avoiding the need for arterial sampling and metabolite analysis.…”

“…Except for 18 F-MNI-444 and 11 C-preladenant, A 2A receptor quantification using these tracers is challenging because of the low specific-to-nonspecific binding ratio or high extrastriatal binding. 18 F-MNI-444 was tested in rhesus monkeys and humans and demonstrated good brain penetration, with the BP ND ranging from 2.6 to 4.9 in A 2A receptor-rich regions (15,16). On the other hand, 11 C-preladenant has a striatal BP ND of around 5.5 and fast tracer kinetics such that a 60-min acquisition is sufficient for accurate A 2A receptor quantification in rat brain.…”

“…Other A 2A receptor-specific PET ligands that have been developed are 18 F-MNI-444, 11 C-TMSX, 11 C-KW-6002, 11 C-SCH442416, and 11 C-preladenant (16,(23)(24)(25)(26)28,30,34). Except for 18 F-MNI-444 and 11 C-preladenant, A 2A receptor quantification using these tracers is challenging because of the low specific-to-nonspecific binding ratio or high extrastriatal binding.…”

“…Several PET radiotracers have been developed and evaluated for in vivo imaging of the A 2A receptor in the brain (15)(16)(17)(18)(19)(20)(21)(22)(23) 18 F-FPSCH, respectively) ( Fig. 1) and evaluated them in healthy rats (6).…”

Imaging of microglial activation in MS using PET: Research use and potential future clinical application

“…39 Other A2AR-binding tracers with more favourable imaging properties and specific binding have been developed, and will hopefully soon be evaluated for their usefulness in imaging of neuroinflammation. 42 Importantly, findings from EAE experiments suggest that A2AR might play a role in controlling inflammation in MS. 43,44 Other targets. Several other promising targets that have not yet been utilized in MS imaging, have emerged in the field of neuroinflammation imaging.…”