¹⁸F-FPEB, a PET Radiopharmaceutical for Quantifying Metabotropic Glutamate 5 Receptors: A First-in-Human Study of Radiochemical Safety, Biokinetics, and Radiation Dosimetry

Abstract

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.

Preclinical Evaluation and Quantification of 18F-FPEB as a Radioligand for PET Imaging of the Metabotropic Glutamate Receptor 5

“…This pattern is similar to the one reported in humans by Wong et al but slower than in monkeys (5,18). The detection of only 1 polar radiometabolite by Hamill et al, however, could suggest that the radiometabolite eluting directly before the parent fraction (Fig.…”

“…Acknowledging this situation, Wong et al optimized the cumbersome and low productive radiosynthesis of 18 F-FPEB (3-18 F-fluoro-5-(2-pyridinylethynyl)benzonitrile) by simplifying the process and increasing the radioactive yield. They additionally performed an in vivo distribution study in humans, which confirmed the previously described pharmacokinetics (5). Recent preliminary preclinical evaluation of 18 F-FPEB has shown promising results, but a thorough validation for preclinical use has not been reported yet (6).…”

Relationship between In Vivo Receptor Occupancy and Efficacy of Metabotropic Glutamate Receptor Subtype 5 Allosteric Modulators with Different In Vitro Binding Profiles

“…The highly selective mGlu 5 allosteric radioligand [ 18 F]FPEB binds to an allosteric site on mGlu 5 that is occupied by the prototypical mGlu 5 NAM, 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), and is being used to assess mGlu 5 occupancy in multiple clinical studies Russell, 2014;Wang et al, 2007;Wong et al, 2013). It is clear that allosteric modulators can bind to multiple topographically distinct allosteric sites on mGlu 5 Gregory et al, 2013).…”

Whole-Body Radiation Dosimetry of 11C-Carbonyl-URB694: A PET Tracer for Fatty Acid Amide Hydrolase

“…1) and the rapid metabolism of O-arylcarbamates compounds (i.e., CURB/URB694) where half of the parent compound is metabolized in the first 20 m after injection (8). The gallbladder timeactivity curve is not uniformly reported in other dosimetry papers but is not unique to 11 C-CURB (18,19). The large variance in gallbladder uptake of radioactivity observed is attributed to variable hepatobiliary clearance and gallbladder emptying among the subjects.…”