Research ArticleClinical Investigations

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

Ansel T. Hillmer, Dustin W. Wooten, Alisha K. Bajwa, Andrew T. Higgins, Patrick J. Lao, Tobey J. Betthauser, Todd E. Barnhart, Howard A. Rowley, Charles K. Stone, Sterling C. Johnson, Jogeshwar Mukherjee and Bradley T. Christian
Journal of Nuclear Medicine December 2014, 55 (12) 1973-1979; DOI: https://doi.org/10.2967/jnumed.114.145151

Abstract

The serotonin-1A (5-HT1A; 5-HT is 5-hydroxytryptamine) receptor is implicated in an array of neurologic 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 6 healthy volunteers (4 women, 2 men; age, 22–38 y). Scans were initiated with the injection of 192–204 MBq of radiotracer, and data were acquired for 2 h. 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 2 wk later for 4 subjects. Regional binding potentials (BPNDs) were calculated with the multilinear reference tissue model, and voxelwise 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 a peak standardized uptake value (SUV) of 1.7. Rapid washout in the cerebellum resulted in SUVs of 0.2 at 120 min, whereas regions with specific 5-HT1A binding exhibited retention of radioligand, yielding SUVs of 0.4–0.9 at 120 min. 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 the insular cortex and 0.7–1.0 in other cortical regions. Stable BPND estimates were obtained using 90 min 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.

The neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) is a crucial regulator of many cognitive processes including memory, learning, and mood. The 5-HT1A receptor is a G-protein–coupled receptor that plays a vital role in regulating 5-HT transmission. These receptors occur presynaptically as autoreceptors in the raphe nuclei (1) and postsynaptically in cortical and hippocampal regions (2). Brain regions rich in 5-HT1A receptor concentrations include the mesial temporal lobe (MTL), cingulate cortex, raphe nuclei, frontal cortex, and parietal cortex. The 5-HT1A receptor is implicated in a variety of neuropsychiatric pathologies, including schizophrenia, Alzheimer disease, depressive disorders, and alcohol dependence.

An important experimental technique for in vivo interrogation of 5-HT1A receptors is PET imaging. To date, the most commonly used PET antagonist radioligand for 5-HT1A receptors is 11C-WAY-100635 (3). This radioligand exhibits high signal in regions of specific binding relative to the cerebellum and suitable regional binding potential (BPND) quantification; however, widespread use of this radioligand has been limited. The radiochemical production for 11C-WAY-100635 is difficult to reliably perform, and the short 20-min half-life of the 11C label requires an on-site cyclotron and yields poor counting statistics toward the end of scanning procedures. To overcome these issues, a variety of WAY-100635 analogs with the longer-lived 18F label (110-min half-life) have been developed (4). 2′-methoxyphenyl-(N-2′-pyridinyl)-p-18F-fluorobenzamidoethylpiperazine (18F-MPPF) has been successfully used to study 5-HT1A physiology in human subjects but suffers from poor brain penetration and subsequently yields low target-to-background ratios (5). 18F-FCWAY has kinetic properties similar to 11C-WAY-100635 and a simple labeling procedure (6). However, defluorination of 18F-FCWAY in vivo resulted in bone uptake of 18F-fluoride ions, complicating analysis of PET data (7) and requiring enzyme inhibitors to enable suitable quantification (8).

The radioligand N-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(4-18F-fluoromethylcyclohexane)carboxamide was designed to provide an 18F-labeled analog of 11C-WAY-100635 with improved stability by moving the radiolabel from an aromatic ring to a primary carbon. Studies of the cis and trans isomers of this radioligand revealed high specificity of the trans isomer for 5-HT1A receptors (9); therefore, this human study focused on the trans isomer, shown in Figure 1 (henceforth abbreviated as 18F-mefway). 18F-mefway is produced with high yields (10), and preclinical experiments demonstrated comparable kinetic properties between 11C-WAY-100635 and 18F-mefway in rhesus monkeys with no evidence of defluorination (11).

FIGURE 1.
FIGURE 1.

Chemical structure of trans-18F-mefway.

Studies investigating 5-HT1A receptor physiology in nonhuman primates using 18F-mefway have also been performed in our laboratories. These findings include sex-based differences in 5-HT1A function, for which increased in vivo affinity of 18F-mefway for the 5-HT1A receptor and decreased 5-HT1A binding potentials in women relative to men were observed (12). Additionally, decreased 5-HT1A binding levels in 5-HTTLPR s-carriers (13) and increased 5-HT1A binding levels after chronic alcohol self-administration have been reported (14). These 18F-mefway studies therefore indicated great promise of a suitable 18F-labeled radioligand to image 5-HT1A–specific physiology in humans.

The goal of this work was to evaluate the in vivo properties of 18F-mefway in humans for the first time. The regional distribution of 18F-mefway uptake and binding in the human brain is reported, including a detailed inspection of 18F-mefway binding in the MTL, an important region with high 5-HT1A density. Furthermore, a preliminary analysis of 18F-mefway’s behavior in venous plasma samples is performed.

MATERIALS AND METHODS

Subjects

Subjects were healthy volunteers consisting of 4 women and 2 men, ranging in age from 22 to 38 y, recruited at the University of Wisconsin–Madison. The University of Wisconsin Institutional Review Board approved all study procedures. All subjects provided informed signed consent forms before participation. Antidepressive medication was verbally screened for as an exclusion criterion.

Scanning Procedures

18F-mefway was produced following previously published methods (9). The synthesis consisted of a nucleophilic substitution of the precursor, N-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridyl)-N-(trans-4-tosyloxymethylcyclohexane)carboxamide (tosyl-trans-mefway; Huayi Isotopes), with cyclotron-produced 18F-fluoride ions at 96°C to synthesize 18F-mefway. Reversed-phase C18 high-performance liquid chromatography purification with a mobile phase of 50:50:0.1 MeCN:H2O:triethylamine was then performed. Solvents were removed via C18 sep-pak extraction. The final product was formulated in 9 mL of sterile saline and 1 mL of EtOH and filter-sterilized.

18F-mefway PET data were acquired on an EXACT HR+ PET scanner (Siemens) using 3-dimensional mode. A 6-min transmission scan using 68Ge rod sources was first acquired for attenuation correction. Dynamic PET data acquisition was initiated with a bolus injection of 192–204 MBq of 18F-mefway, and data were acquired for 120 min. Venous samples of 1.0 mL were acquired from the cephalic vein (opposite the injection arm) approximately 5, 15, 30, 60, 90, and 120 min after injection. At least 2 wk after the first scan, 5 of the 6 subjects returned for a second 18F-mefway scanning procedure to assess the test–retest reproducibility of 18F-mefway imaging. The mean and SD of the administered mass of 18F-mefway was 56 ± 50 ng (range, 12–143 ng). The mean administered activity of 18F-mefway was 199 ± 4 MBq (range, 192–204 MBq). There were no adverse or clinically detectable pharmacologic effects, including no significant changes to vital signs or laboratory results, in any of the 6 subjects.

MR imaging data were acquired on a 3.0-T MR750 scanner (GE Healthcare) with an 8-channel head coil. A T1-weighted Spoiled Gradient REcalled Acquisition volume was acquired using the following parameters: inversion time/echo time/repetition time, 450/3.2/8.2 ms; flip angle, 12°; slice thickness, 1 mm no gap; field of view, 256; and matrix size, 256 × 256.

Data Processing and Analysis

Venous blood samples were analyzed to assay 18F-mefway metabolism in vivo. Samples of 1.0 mL of whole blood mixed with 50 μL of heparinized saline were centrifuged for 5 min. Next, 0.5 mL of plasma was extracted and mixed with 50 μL of 5.5% sodium bicarbonate and 0.5 mL of acetonitrile, followed by vigorous mixing to denature the proteins. After the protein precipitate settled, 0.5 mL of liquid was extracted, concentrated, and spotted on an alumina thin-layer chromatography (TLC) plate (Whatman). The TLC plate was developed in a mobile phase of 50:50 MeOH:10% ammonium acetate and subsequently exposed to a phosphor plate to quantify parent 18F-mefway present in the blood. The phosphor plate was read by a Cyclone storage phosphor system (PerkinElmer) and analyzed with OptiQuant software. The plasma-free fraction (fP) was measured with Centrifree ultrafiltration units (Millipore).

PET data were histogrammed into frames of 8 × 0.5, 3 × 2, 10 × 5, and 6 × 10 min. Sinogram data were then reconstructed with a filtered backprojection algorithm (Direct Inverse Fourier Transformation) using a 4-mm gaussian filter and included corrections for random events, deadtime, signal attenuation, and scanner normalization. Final images had dimensions of 128 × 128 × 63, corresponding to voxel dimensions of 2.57 × 2.57 × 2.43 mm. Images of PET data summed from 1 to 10 min after injection, reflective of diffuse radioligand delivery throughout the brain, were used to register PET frames to the native space of the corresponding MR image using FSL’s (Functional MRI of the Brain Software Library) Linear Image Registration Toolbox (15). The affine matrix was constrained to a rigid-body transformation (6 degrees of freedom.) because no intrasubject normalization was imposed.

Regions of interest were defined with FreeSurfer 5.3 software (http://surfer.nmr.mgh.harvard.edu). Regions extracted with this template-based algorithm included the amygdala, hippocampus, parahippocampal gyrus, insular cortex, anterior cingulate gyrus, posterior cingulate gyrus, parietal cortex, orbitofrontal cortex, temporal cortex, occipital cortex, and frontal cortex, shown in Figure 2. Additionally, the raphe nuclei region was manually drawn for each PET scan because this region’s structure cannot be accurately determined using MR imaging data. To observe radioligand kinetic properties in regions of highest 18F-mefway binding, PET data from a manually defined region of focal uptake in the MTL were also analyzed. This region included areas of the hippocampus proper, subiculum, dentate gyrus, and amygdala and was hand-drawn to minimize imperfect PET to MR imaging coregistration and partial-volume effects. Time–activity curves were extracted from all regions for subsequent analysis.

FIGURE 2.
FIGURE 2.

Regions used for analysis of 18F-mefway PET data. Regions defined by template-based FreeSurfer algorithm included amygdala (Am), hippocampus (Hp), parahippocampal gyrus (pHp), insular cortex (IC), anterior cingulate gyrus (aCG; not shown), posterior cingulate gyrus (pCG), parietal cortex (PC), orbitofrontal cortex (OfC), temporal cortex (TC), occipital cortex (OC), frontal cortex (FC), and cerebellum (CB). Hand-drawn raphe nuclei (RN) is also shown.

To compare measured cerebral radioactivity concentrations with other radioligands, the standardized uptake value (SUV) was calculated as SUV = PET/i.d. × mass × 1,000, where PET is the measured PET concentration (kBq/cm3), i.d. is the injected dose (kBq), and mass is subject mass (kg). To quantify specific 18F-mefway binding, binding potential based on nondisplaceable uptake (BPND) was measured. BPND is an index of receptor binding proportional to the product of receptor density (Bmax) and radioligand–receptor affinity (1/KDapp) as BPND = fNDBmax/KDapp, where fND is the free fraction of nondisplaceable radioligand in the tissue (16). Regional 18F-mefway BPND values were calculated with the multilinear reference tissue model (MRTM) (17), assuming the cerebellum as a reference region. Logan graphical analysis (18) was used to calculate BPND values for comparison with the MRTM method and to visualize the establishment of radioligand psuedoequilbirum. Voxelwise 18F-mefway BPND maps were also produced with Logan graphical analysis.

To assess the test–retest reproducibility of 18F-mefway binding, early PET data from the retest scans (1–10 min after injection) were coregistered to the space of the test PET scan, allowing for 6 degrees of freedom. The affine matrix transforming the test PET data to the MR imaging was then applied to the retest PET data. Time–activity curves were extracted, and regional BPND values using MRTM were calculated as described above. The test–retest variability (TRV) between test and retest BPND values expressed as a percentage was calculated for each region with the relationship TRV = Abs{(BPND(Test) − BPND(Retest))/(BPND(Test) + BPND(Retest))/2} × 100. Additionally, the intraclass correlation coefficient (ICC) (19) was calculated for each region.

RESULTS

Radiochemistry

18F-mefway was produced with high yields greater than 1 GBq, with specific activities greater than 400 MBq/nmol. Radiochemical purity was 98.7% ± 2.8%, with chemical purities and stability greater than 90% at the time of expiration.

18F-Mefway in Plasma

Venous blood samples were acquired to characterize the in vivo metabolism of 18F-mefway. Acceptable radiochromatograms were acquired only for 4 subjects. Radio-TLC analysis of the plasma samples revealed the presence of radiolabeled metabolites as shown in Figure 3, although no attempt was made to assess any volatile species. The chemical nature of these metabolites was not characterized in the present work. Notably, no radiolabeled species were detectable at the origin of the chromatogram, suggesting negligible accumulation of 18F-fluoride ions in the blood.

FIGURE 3.
FIGURE 3.

Metabolism of 18F-mefway in vivo. Main plot shows percentage of total radioactivity in plasma attributed to parent 18F-mefway. Each distinct color and shape corresponds to separate subject. Inset presents typical radiochromatogram. There is absence of detectable radioactivity at origin, expected location of 18F-fluoride ion elution.

In vivo metabolism of 18F-mefway was initially rapid, with parent compound accounting for less than 20% of total plasma radioactivity 30 min after injection. At this point, metabolism slowed, such that 10%–15% of the radioactivity in the plasma was 18F-mefway at 90 min after injection (Fig. 3). The fP of 18F-mefway, measured for 5 of the 6 subjects, was 5.1% ± 0.7%.

18F-Mefway Brain Uptake

Time–activity curves of 18F-mefway uptake in the brain are illustrated in Figure 4. The time course of 18F-mefway in the brain rapidly peaked at SUVs of roughly 1.7 after 1–2 min in the cerebellum and various cortical regions. Clearance of 18F-mefway was rapid in the cerebellum, decreasing to half the peak value within 10 min after injection and approaching SUVs of 0.2 at 120 min after injection. In regions of high specific 18F-mefway uptake, such as the MTL and hippocampus, peak uptake of 18F-mefway was slower, plateauing within 15–20 min after injection with slow decreases in PET signal, reflective of specific 18F-mefway binding. As illustrated in Figure 5A, ratios of 18F-mefway concentrations in hippocampal regions relative to the cerebellum plateaued at roughly 60–90 min after injection at ratios ranging from 2 to 4.5. In cortical regions, these ratios plateaued faster with lower peak ratio values.

FIGURE 4.
FIGURE 4.

Representative 18F-mefway time–activity curves. SUVs are defined as SUV = PET/i.d. × weight × 1,000. Regions shown include focal areas of uptake in MTL, hippocampus (HP), anterior cingulate gyrus (aCG), raphe nuclei (RN), occipital cortex (OC), and cerebellum (CB). i.d. = injected dose.

FIGURE 5.
FIGURE 5.

Kinetic properties of 18F-mefway in vivo. (A) 18F-mefway target-to-cerebellum ratios. (B) Logan plots, with t* = 45 min, to visualize pseudoequilibrium of tracer in various regions of brain. Regions shown include focal areas of uptake in MTL, hippocampus (Hp), anterior cingulate gyrus (aCG), raphe nuclei (RN), and occipital cortex (OC).

Specific 18F-Mefway Binding

Estimates of BPND generated with MRTM2 for all regions examined are presented in Table 1. The highest values were observed in the MTL (2.42 ± 0.46). Estimates of BPND generated with the Logan reference region analysis method, using a linearization time t* = 45 min and omitting the Embedded Image term, agreed within 3% of the estimates with MRTM. Sample Logan plots are illustrated in Figure 5B, showing the linearization of the data in all regions by 45 min after injection. A voxelwise BPND map, generated with Logan graphical analysis, is shown in Figure 6 for visualization of 18F-mefway specific binding.

View this table:
TABLE 1

Scan Details and Regional 18F-Mefway BPND Values with Test–Retest Analysis

FIGURE 6.
FIGURE 6.

Voxel-wise 18F-mefway BPND maps overlaid on coregistered MR image. Parametric BPND images are linearly scaled from 0 to 3.5. Location of each transverse slice is denoted by red lines on midsagittal slice at bottom right.

Retest 18F-mefway scans were acquired for 5 subjects; however, 1 subject did not complete the scanning procedure, therefore only 4 retest scans were analyzed for test–retest analysis. For the 4 subjects with retest scans, the TRV averaged across all regions was 8% (Table 1). The ICC in regions of high 18F-mefway uptake was greater than 0.88, indicating substantial agreement (20). Lower values were measured in areas of moderate uptake, likely due to the reduced BPND values in these regions.

DISCUSSION

This study demonstrates that 18F-mefway has favorable specific binding levels and kinetic properties for human PET imaging of 5-HT1A receptors. Reliable imaging of the 5-HT1A system has been an important goal of the neuroimaging community, yet lack of a suitable radioligand has stunted successful widespread PET imaging of 5-HT1A receptors due to limitations in areas such as radiochemistry, quantitation, defluorination, and brain penetration. 18F-mefway possesses a simple radiochemical production, brain uptake levels comparable to other 5-HT1A radioligands, a high signal-to-noise ratio, suitable kinetic properties, no apparent PET signal in bone, and higher detected nonspecific PET signal than 11C radioligands, making it a promising candidate for imaging 5-HT1A receptors in humans.

Radio-TLC techniques were used to measure the rate of 18F-mefway metabolism in vivo. The results indicated initial rapid metabolism of 18F-mefway, followed by a slow metabolism component such that 10%–15% of the radioactivity in the plasma was attributed to parent 18F-mefway after 90 min in the blood. Low counting statistics in the blood samples at late times due to rapid metabolism and low fP limited the precision of these measurements. The rate of 18F-mefway metabolism was slightly slower than 11C-WAY-100635 and 18F-FCWAY (21, 22).

The in vivo metabolism of 11C-WAY-100635 and 18F-FCWAY results in radiolabeled cyclohexanecarboxylic acid species, both of which crossed the blood–brain barrier (21,22). A similar potential metabolite species of 18F-mefway, 18F-trans-4-fluoromethylcyclohexanoic acid, showed little to no brain penetration in rat PET studies (23). We have not fully characterized the metabolite species of 18F-mefway in humans for the present work; thus, the potential for 18F-trans-4-fluoromethylcyclohexanoic acid accumulation in the human brain remains a matter for future studies. The fP of 18F-mefway was measured at 5.1%, with little variability between subjects. This low free fraction is consistent with the values of other radioligands specific to 5-HT1A receptors.

Specific uptake of 18F-mefway in the human brain was consistent with the cerebral distribution of 5-HT1A receptors (24). The highest measured 18F-mefway BPND levels were 2.4 in the regions in the MTL, with values of 1.6 in the insular cortex, 1.2 in the anterior cingulate gyrus, 0.8 in the raphe nuclei, and 0.6–0.9 in the occipital cortex. These human 18F-mefway BPND values are roughly 3–4 times lower than reported 11C-WAY-100635 BPND values derived using an atlas-based approach (25). However, a direct comparison of these radioligands in human subjects with the same scanners and data processing techniques will be needed to identify in vivo differences between radiotracers. Such studies previously performed in nonhuman primates demonstrated comparable levels of BPND between 18F-mefway and 11C-WAY-100635 (11). Although interspecies differences may explain some of the variation in 18F-mefway binding between humans and monkeys, the atlas-based ROI definition in this work likely reduced BPND because of spatial averaging, compared with the manual ROI definition in our previous work.

The behavior of 5-HT1A–specific radioligands in the cerebellum is a crucial issue for accurate assay of 5-HT1A binding. Use of the cerebellum with reference region analysis strategies can avoid the need for arterial blood sampling. The cerebellum has been used as a reference region for quantitation of BPND with 5-HT1A radioligands because of minimal specific binding levels (26). Small levels of specific 11C-WAY-100635 binding were subsequently observed in the cerebellar gray matter and vermis (27), indicating a potential underestimation in BPND with cerebellar gray matter. White matter regions have been proposed as potential reference regions to avoid this bias of BPND estimates (28,29), which assumes similar nonspecific radioligand behavior in both white matter and gray matter. We speculate that the strategies developed to account for potential binding of other 5-HT1A radioligands in the cerebellum will be applicable to 18F-mefway procedures as well. Further investigation is needed to fully characterize potential specific binding in the cerebellum and its ramifications on the analysis of 18F-mefway PET data.

The time course of 18F-mefway in the cerebellum was characterized by rapid washout, followed by low radioactivity concentrations (Fig. 4). These cerebellar characteristics are similar for other 5-HT1A radioligands, resulting in low counting statistics in the cerebellum at late times. Such regions are subject to bias depending on the scatter correction and reconstruction algorithms used in processing the PET data (30) and subsequently bias BPND estimates when used as reference regions. Given the similar cerebellar SUVs of 18F-mefway and 11C-WAY-10036 (31) at 90 min, the 110-min half-life of the 18F isotope, compared with the 20-min half-life of 11C, yields more than 12-fold more real measured counts by the PET scanner. This characteristic, and the opportunity to conduct PET studies with an off-site cyclotron, are important practical advantages of 18F-labeled 5-HT1A radioligands. One potential cause of low cerebellar uptake for 5-HT1A–specific radioligands is the P-glycoprotein transporter, as demonstrated for 18F-MPPF (32,33). The potential regulation of 18F-mefway brain penetration by P-glycoprotein is an important question for future investigation.

Previous 18F-FCWAY studies exhibited bone uptake of 18F-fluoride ions, resulting in the spill-in of detected PET signal from the surrounding skull into the cerebellum and subsequently requiring the use of enzyme inhibitors for accurate 18F-FCWAY quantification (7,8). Low levels of PET signal in bone were evident in rat 18F-mefway studies (34) but not in rhesus monkeys (11). The present data were closely inspected for potential bone uptake of radiolabeled species in human subjects. The PET images did not indicate any areas of elevated 18F-mefway uptake in regions immediately surrounding the brain. Cerebellar time–activity curves decreased at late times, instead of plateauing or increasing (which would reflect the spill-in of PET signal from surrounding bone). Furthermore, the radio-TLC analysis did not reveal a detectable signal at the expected location of 18F-fluoride ion elution (the origin; Fig. 3A). These studies provide evidence for negligible accumulation of radiolabeled species in bone; however, they are not conclusive. Future planned PET/CT studies, providing accurate localization of the skull, will conclusively determine the reported absence of bone uptake.

Typical 11C-WAY-100635 scans require 90 min for accurate quantification. Although 120 min of 18F-mefway data were acquired for the present scans, the data were truncated at 90 min and BPND values were recalculated with MRTM. Calculated BPND from the 90-min truncated dataset agreed well with BPND from the full dataset, with an R2 of 0.99. There was a slight negative bias due to a systematic BPND underestimation of 3% in the MTL regions of highest 18F-mefway binding. This small bias in regions of extreme 18F-mefway binding may be acceptable in exchange for reduced duration of scanning procedures. Therefore, it is likely that 90 min will be an appropriate scanning time for accurate quantification of 18F-mefway binding.

Values of 18F-mefway TRV averaged 8% across all regions, indicating good agreement in repeated scans. The ICC values were strong in regions of high 18F-mefway binding. Reduced ICC values were observed in regions of lower 18F-mefway specific binding, likely due to lower BPND values in these regions. The test–retest properties of 18F-mefway are encouraging for future human PET studies implementing a 2-scan experimental design.

The binding profile of 18F-mefway allowed for close inspection of the regional distribution of specific binding in the MTL, as visualized in Figure 7. The region of highest 18F-mefway binding was the hippocampus. Relatively lower binding levels were observed in the subiculum sublayer, located more medially than CA1–CA4, and the amygdala. Less 18F-mefway binding was also evident in the parahippocampal gyrus and the most posterior regions of the hippocampus near the crux of the fornix. These differences in specific 18F-mefway uptake yielded exquisite delineation of 5-HT1A binding in the MTL. Consequently, 18F-mefway PET data from this region, most prominently in the hippocampus, may have clinical utility in studying both healthy pathology and neurologic and psychiatric disorders that affect the MTL.

FIGURE 7.
FIGURE 7.

Delineation of specific 18F-mefway binding in MTL. (Top) T1-weighted MR image with corresponding hippocampal FreeSurfer mask drawn in red. (Bottom) 18F-mefway BPND parametric image overlaid on same MR image. BPND linear thresholding ranges from 1.5 to 4.5. Red lines on far right sagittal slice indicate location of corresponding coronal slices.

CONCLUSION

These initial studies of 18F-mefway in humans prove highly promising. The simple radiochemical production, high specific radioligand uptake, 18F radiolabel, and lack of PET signal in bone make 18F-mefway a promising candidate for assay of 5-HT1A receptors with human PET. Future studies to assess the viability of 18F-mefway in pathology-specific populations are merited.

DISCLOSURE

The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734. Support for this research was provided by R33AG030524, T32CA009206, and P30HD03352. No other potential conflict of interest relevant to this article was reported.

Acknowledgments

We thank R. Jerry Nickles and Hector Valdovinos for assistance with radioisotope production, Dr. Dhanabalan Murali for assistance with radiochemical production of 18F-mefway, and Dr. Steve Kecskemeti for assistance with MRI data acquisition and processing. Sharon Kuruvilla provided important assistance with figure preparation. We are grateful to Barb Mueller and Travis Doran for their contributions with scanning procedures and to the volunteer subjects for their participation in this study.

Footnotes

  • Published online Nov. 11, 2014.

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  • Received for publication July 7, 2014.
  • Accepted for publication September 30, 2014.
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