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Identification of safe and valid PET radioligands for metabotropic glutamate receptor, type 5 (mGluR5), is essential to measure changes in brain mGluR5 in neuropsychiatric disorders, to confirm central mGluR5 occupancy of drug candidates, and to guide dose selection for obtaining an optimum therapeutic window. Here we present the results of a first-inhuman study assessing the safety and effectiveness of a novel PET radiopharmaceutical, 18 F-3-fluoro-5-[(pyridin-3-yl)ethynyl] benzonitrile ( 18 F-FPEB), for quantifying regional brain concentrations of mGluR5. Methods: Quantification of whole-body biokinetics was conducted in 6 healthy adults (3 men and 3 women). The radiation safety profile was estimated with OLINDA/EXM software. Subsequently, pairs of dynamic brain scans were obtained for 11 healthy men to identify optimal methods for derivation of regional distribution volume and binding potential and to determine the repeatability of measurement. Results: The whole-body effective radiation dose was approximately 17 mSv/MBq (62 mrem/mCi), with the gallbladder receiving the highest dose of 190 mSv/MBq. In brain studies, time-activity curves showed high accumulation in the insula/caudate nucleus, moderate uptake in the thalamus, and the lowest concentration in the cerebellum/pons. The plasma reference graphical analysis method appeared optimal for 18 F-FPEB; it showed acceptable test-retest variability of nondisplaceable binding potential (,10%) and identified the highest nondisplaceable binding potential values (from ;0.5 in the globus pallidus to ;3.5 in the insula) for target regions. Safety assessments revealed no clinically meaningful changes in vital signs, electrocardiogram, or laboratory values. Conclusion: 18 F-FPEB is safe and well tolerated, and its regional cerebral distribution is consistent with previous reports in the literature for metabotropic glutamate receptors. The repeatability of measurement suggests that 18 F-FPEB is suitable for quantifying mGluR5 in humans.

disease (HD) striatal neuron loss precedes and predicts motor signs or symptoms. Current imaging biomarkers lack adequate sensitivity for assessing the early stages of HD. Developing an imaging biomarker for HD spanning the time of onset of motor signs remains a major unmet research need. Intracellular proteins whose expression is altered by the mutant huntingtin protein may be superior markers for early HD stages.OBJECTIVE To evaluate whether [ 18 F] ]fluoroethoxy)phenyl)-7methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione), a novel phosphodiesterase 10 positron emission tomography (PET) ligand, is a sensitive marker for striatal changes in early HD. DESIGN, SETTING, AND PARTICIPANTSA cohort of individuals with HD, including premanifest (pre-HD) or manifest with motor signs (mHD), underwent clinical assessments, genetic determination, [ 18 F]MNI-659 PET imaging, and brain magnetic resonance imaging. Age-matched healthy volunteers (HVs) also received clinical assessments and PET and magnetic resonance imaging. MAIN OUTCOMES AND MEASURESBinding potentials (BPnds) were estimated for brain regions of interest, specifically within the basal ganglia, and compared between participants with HD and the HVs and correlated with markers of HD severity and atrophy of basal ganglia nuclei.RESULTS Eleven participants with HD (8 mHD and 3 pre-HD) and 9 HVs participated. Ten of 11 HD participants had known huntingtin CAG repeat length, allowing determination of a burden of pathology (BOP) score. One individual with HD declined CAG determination. All participants with mHD had relatively early-stage disease (4 with stage 1 and 4 with stage 2) and a Unified Huntington's Disease Rating Scale (UHDRS) total Motor subscale score of less than 50. The HD cohort had significantly lower striatal [ 18 F]MNI-659 uptake than did the HV cohort (mean, −48.4%; P < .001). The HD cohort as a whole had a reduction in the basal ganglia BPnd to approximately 50% of the level in the HVs (mean, −47.6%; P < .001). The 3 pre-HD participants had intermediate basal ganglia BPnds. Striatal [ 18 F]MNI-659 uptake correlated strongly with the severity of disease measured by the clinical scale (UHDRS Motor subscale; R = 0.903; P < .001), the molecular marker (BOP; R = 0.908; P < .001), and regional atrophy (R = 0.667; P < .05). CONCLUSIONS AND RELEVANCEAs a promising striatal imaging biomarker, [ 18 F]MNI-659 is potentially capable of assessing the extent of disease in early mHD. Furthermore, [ 18 F]MNI-659 may identify early changes in medium spiny neurons and serve as a marker to predict conversion to mHD. Additional studies with larger, stratified cohorts of patients with HD and prospective studies of individuals with pre-HD are warranted.

Phosphodiesterase (PDE) 10A is an enzyme involved in the regulation of cyclic adenosine monophosphate and cyclic guanosine monophosphate and is highly expressed in medium-sized spiny neurons of the striatum, making it an attractive target for novel therapies for a variety of neurologic and psychiatric disorders that involve striatal function. Potential ligands for PET imaging of PDE10A have been reported. Here, we report the first-in-human characterization of 2 new PDE10A radioligands, 2-(2-(3-(1-(2-fluoroethyl)-1H-indazol-6-yl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ( 18 F-MNI-654) and 2-(2-(3-(4-(2-fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ( 18 F-MNI-659), with the goal of selecting the best one for use in future studies interrogating pathophysiologic changes in neuropsychiatric disorders and aiding pharmaceutical development targeting PDE10A. Methods: Eleven healthy volunteers participated in this study ( 18 F-MNI-654 test-retest, 2 men; 18 F-MNI-659 test-retest, 4 men and 1 woman; 18 F-MNI-659 dosimetry, 2 men and 2 women). Brain PET images were acquired over 5.5 h for 18 F-MNI-654 and over 3.5 h for 18 F-MNI-659, and pharmacokinetic modeling with plasma-and reference-region (cerebellar cortex)-based methods was performed. Whole-body PET images were acquired over 6 h for 18 F-MNI-659 and radiation dosimetry estimated with OLINDA. Results: Both radiotracers were similarly metabolized, with about 20% of intact parent remaining at 120 min after injection. PET time-activity data demonstrated that 18 F-MNI-654 kinetics were much slower than 18 F-MNI-659 kinetics. For 18 F-MNI-659, there was good agreement between the Logan and simplified reference tissue models for nondisplaceable binding potential (BP ND ), supporting noninvasive quantification, with test-retest variability less than 10% and intraclass correlation greater than 0.9. The 18 F-MNI-659 effective dose was estimated at 0.024 mSv/MBq. Conclusion: PET imaging in the human brain with 2 novel PDE10A 18 F tracers is being reported. Noninvasive quantification of 18 F-MNI-659 with the simplified reference tissue model using the cerebellum as a reference is possible. In addition, 18 F-MNI-659 kinetics are fast enough for a good estimate of BP ND with 90 min of data, with values around 3.0 in the basal ganglia. Finally, 18 F-MNI-659 dosimetry is favorable and consistent with values reported for other PET radiotracers currently used in humans.