Comparative assessment of ¹⁸F‐Mefway as a serotonin 5‐HT_1A receptor PET imaging agent across species: Rodents, nonhuman primates, and humans

Abstract

We have developed 18F-trans-Mefway (18F-Mefway) for PET imaging studies of serotonin 5-HT1A receptors which are implicated in various brain functions. Translation of imaging the 5-HT1A receptor in animal models to humans will facilitate an understanding of the role of the receptor in human brain disorders. We report comparative brain distribution of 18F-Mefway in normal mice, rats, monkeys and healthy human volunteers. Mefway was found to be very selective with subnanomolar affinity for the serotonin 5-HT1A receptor. Affinities of >55 nM were found for all other human-cloned receptor subtypes tested. Mefway was found to be a poor substrate (>30 μM) for the multidrug resistance 1 protein, suggesting low likelihood of brain uptake being affected by P-glycoprotein. Cerebellum was used as a reference region in all imaging studies across all species due to the low levels of 18F-Mefway binding. Consistent binding of 18F-Mefway in cortical regions, hippocampus and raphe was observed across all species. 18F-Mefway in the human brain regions correlated with the known postmortem distribution of 5-HT1A receptors. Quantitation of raphe was affected by the resolution of the PET scanners in the rodents, while monkeys and humans showed a raphe to cerebellum ratio approximately 3. 18F-Mefway appears to be an effective serotonin 5-HT1A receptor imaging agent in all models including humans. 18F-Mefway therefore may be used to quantify serotonin 5-HT1A receptor distribution in brain regions for the study of various CNS disorders.

Human brain imaging of nicotinic acetylcholine α4β2* receptors using [18F]Nifene: Selectivity, functional activity, toxicity, aging effects, gender effects, and extrathalamic pathways

“…Across the various species, [ 18 F]Nifene exhibited selective targeting to α4β2* receptors, lack of toxicity, suitable dosimetry, rapid kinetics, quantifiable in PET studies, with the potential of becoming available for large multicenter trials. As previously discussed for [ 18 F]Mefway (Mukherjee et al, ), such properties facilitate the translation of [ 18 F]Nifene to human research and clinical studies.…”

“…Our previously reported biological properties of [ 18 F]Nifene in rodents (Kant et al, ; Bieszczad et al, ), monkeys (Pichika et al, ; Hillmer et al, ), and humans (Lao et al, ) suggest some regional variations of binding of [ 18 F]Nifene in the brain across the different species. Additional constraints in the different species occur due to resolution of scanners for a mouse (∼25 g), rat (∼250 g), monkey (∼10,000 g), and human (∼70,000g) as previously discussed for serotonin 5‐HT 1A receptor imaging agent [ 18 F]Mefway (Mukherjee et al, ).…”

[18F]FDG PET/CT Studies in Transgenic Hualpha-Syn (A53T) Parkinson’s Disease Mouse Model of α-Synucleinopathy

“…Our additional studies in the A53T PD mice model will include studies of the serotonergic 5-HT1A receptors since these receptors may be affected in the hippocampus of A53T PD mice ( Deusser et al, 2015 ). We propose to use [ 18 F]mefway for PET imaging of the serotonin 5-HT1A receptor ( Mukherjee et al, 2016 ). Nicotinic α4β2 receptors play a role in cognitive impairment and may be targets for neuroprotection in PD ( Perez-Lloret and Barrantes, 2016 ).…”

Biodistribution and Radiation Dosimetry of [18F]Mefway in Humans

“…Although many PET radioligands have been developed for imaging 5-HT 1A receptors, majority of them had improper characteristics for clinical studies such as metabolic instability and poor penetration to the brain [5][6][7]. To date, [ 18 F]Mefway is considered as a promising PET tracer because it showed high selective and specificity for the 5-HT 1A receptors [8,9]. In addition, the utility of [ 18 F]Mefway in the animal disease models such as depression and Parkinsonian's were validated [10,11].…”