In Vivo Evaluation of ¹⁸F-MNI698: An ¹⁸F-Labeled Radiotracer for Imaging of Serotonin 4 Receptors in Brain

Abstract

Serotonin 4 receptors (5-hydroxytryptamine receptor 4 [5HT4R]) hold promise as a novel therapeutic approach to multiple brain disorders, including Alzheimer and Huntington disease. In vivo imaging of these receptors with selective 5HT4R radiotracers and PET would be valuable to investigate alterations in 5HT4R in different brain disorders and to assist drug discovery. In this study, 18 F-MNI698 was evaluated as a potential PET radiotracer for imaging of 5HT4R in the brain. Methods: Eighteen PET studies were performed in 3 adult rhesus monkeys. The radiotracer was administered as a bolus intravenous injection or bolus plus constant infusion (time that would be required to inject the bolus at the infusion rate 5 60 min), and arterial blood was collected for data quantification. Kinetic models were used to estimate distribution volumes and binding potentials, for which the cerebellum was used as a reference region. 18 F-MNI698 test-retest variability and upper mass dose limits were determined. Preblocking studies using several doses of SB204070, a selective 5HT4R antagonist, were performed. Results: 18 F-MNI698 avidly entered the monkey brain (peak percentage injected dose of ∼6.6%), and its brain distribution was consistent with known 5HT4R densities. At 120 min after bolus injection and after the start of radiotracer infusion, only less than 5% and approximately 10% parent compound was present in blood, respectively. Measured binding potentials were underestimated by 22%-36% when noninvasive methods were used for data quantification in comparison with invasive methods. A good agreement was found between test-retest measurements. The radiotracer upper mass dose limit (,5% occupancy) was determined to be 13.1 μg per 70 kg of body weight. SB204070 blocked the radiotracer binding in a dose-dependent manner. Conclusion: Data indicate that 18 F-MNI698 is a promising PET radiotracer for imaging of 5HT4R in the brain, and human studies are warranted based on these study results.

Characterization and Reliability of [18F]2FNQ1P in Cynomolgus Monkeys as a PET Radiotracer for Serotonin 5-HT6 Receptors

“…Compared to similar reproducibility studies published for other PET tracers of the serotoninergic system in primates (Chen et al, 2012; Tavares et al, 2014), the reproducibility parameters of [ 18 F]2FNQ1P binding potential showed more satisfactory results. In consequence, the ability to detect changes in 5-HT 6 R availability or occupancy in in vivo studies, would be more sensitive with [ 18 F]2FNQ1P, giving a supplemental chance of elucidating functional and dysfunctional serotonin transmission in the brain and facilitating the development of therapeutic drugs targeting 5-HT 6 Rs.…”

In Vivo Evaluation of 11C-Preladenant for PET Imaging of Adenosine A2A Receptors in the Conscious Monkey

“…4). Furthermore, the A 2A R occupancy at caffeine doses of 2.5, 5, and 10 mg/kg became 70%, 72%, and 81%, respectively, after correction for self-occupancy (16,20). Regardless of possible nonnegligible receptor occupancy by preladenant, our study demonstrated that 11 C-preladenant has suitable binding properties and pharmacokinetic profile, which warrants its translation to human studies.…”

Role of Mast Cells in the Control of Aldosterone Secretion

“…However, the question is whether adrenal glands may actually be viewable through this approach. In this regards, radiolabeled 5-HT4R ligands have successively been used for positron emission tomography (PET) scan imaging in monkeys and humans [95,96]. Interestingly, monkey adrenals have been well visualized in whole-body PET images [97] but such observations are still lacking in man.…”