First-in-Human Evaluation of ¹⁸F-Mefway, a PET Radioligand Specific to Serotonin-1A Receptors

Abstract

The serotonin-1A (5-HT1A) receptor is implicated in an array of neurological and psychiatric disorders. Current PET radioligands targeting 5-HT1A receptors have limitations hindering widespread PET studies of this receptor system. The 5-HT1A specific antagonist radioligand N-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(trans-4-18F-fluoromethylcyclohexane)carboxamide (18F-mefway) exhibited promising in vivo properties in rhesus monkeys. The goal of this work was to examine the in vivo cerebral binding profile and metabolism of 18F-mefway in humans. Methods Dynamic 18F-mefway PET data were acquired for six healthy volunteers (4F, 2M; 22–38 years). Scans were initiated with the injection of 192–204 MBq radiotracer and data were acquired for two hours. Venous blood samples were collected and assayed to examine the in vivo metabolism profile of 18F-mefway. To examine the test-retest variability of 18F-mefway, a second PET scan was acquired at least two weeks later for four subjects. Regional binding potentials (BPND) were calculated with MRTM, and voxel-wise BPND maps were calculated with Logan graphical analysis. Regions surrounding the brain were carefully inspected for uptake of radiolabeled species in bone. Results 18F-Mefway uptake in the brain occurred quickly with peak SUVs of 1.7. Rapid washout in the cerebellum resulted in SUVs of 0.2 at 120 minutes, while regions with specific 5-HT1A binding exhibited retention of radioligand yielding SUVs of 0.4–0.9 at 120 minutes. Rapid metabolism of 18F-mefway was observed, with no detected 18F-fluoride ions in plasma. BPND values of 2.4 were measured in the mesial temporal lobe, with values of 1.6 in insular cortex and 0.7–1.0 in other cortical regions. Stable BPND estimates were obtained using 90 minutes of dynamic data. Average test-retest variability was 8%. No evidence of radioactivity uptake in bone was observed. Conclusion 18F-Mefway exhibits favorable in vivo properties for serotonin 5-HT1A receptor measurements in humans. The simple radiosynthesis, high specific binding profile, and absence of PET signal in bone make 18F-mefway an attractive radiotracer for PET experiments examining the 5-HT1A receptor in neuropsychiatric disorders and drug intervention.

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

“…In addition, little uptake in the bone indicates that [ 18 F]Mefway has metabolic stability against in vivo defluorination in humans. This result was in good correspondence with the previous finding [12,13].…”

“…In addition, the utility of [ 18 F]Mefway in the animal disease models such as depression and Parkinsonian's were validated [10,11]. In initial human studies, [ 18 F]Mefway PET showed reasonable brain uptake without in vivo defluorination [12,13].…”

P-Glycoprotein, not BCRP, Limits the Brain Uptake of [18F]Mefway in Rodent Brain

“…In addition, if majority of a tariquidar is bound to rodent plasma proteins and plasma free fraction of [ 18 F]Mefway is large, the enhancement of brain uptake can be attributed to the effect of tariquidar. However, this hypothesis are unlikely because a plasma free fraction of [ 18 F]Mefway was quantified of 5 or 15 % in monkeys and 5 % in humans, respectively [17,41]. Genetically disrupted mice also showed the increment of brain uptakes in the P-gp knockout mice.…”

“…In humans, Bcrp was expressed at the BBB significantly more highly than P-gp based on mRNA and proteomic analysis [40,42]. Moreover, [ 18 F]Mefway has a higher target-to-reference value than [ 18 F]MPPF and considerably greater metabolic stability against radiodefluorination than [ 18 F]FCWAY in humans [14,17,43,44].…”

“…Later, [ 18 F]Mefway, which has comparably high selectivity and affinity to 5-HT 1A receptors and in vivo metabolic stability against radiodefluorination in humans, was developed to overcome these difficulties. Its efficacy in subjects ranging from rodents to humans has been previously demonstrated [14][15][16][17][18][19][20][21][22][23].…”