TY - JOUR
T1 - 18F-FPEB, a PET radiopharmaceutical for quantifying metabotropic glutamate 5 receptors
T2 - A first-in-human study of radiochemical safety, biokinetics, and radiation dosimetry
AU - Wong, Dean F.
AU - Waterhouse, Rikki
AU - Kuwabara, Hiroto
AU - Kim, Jongho
AU - Brašíc, James R.
AU - Chamroonrat, Wichana
AU - Stabins, Michael
AU - Holt, Daniel P.
AU - Dannals, Robert F.
AU - Hamill, Terence G.
AU - Mozley, P. David
PY - 2013/3/1
Y1 - 2013/3/1
N2 - 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, 18F-3-fluoro-5-[(pyridin-3-yl)ethynyl] benzonitrile ( 18F-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 μSv/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 18F-FPEB; it showed acceptable test-retest variability of nondisplaceable binding potential (<10%) and identified the highest nondisplaceable binding potential values (from ∼.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: 18F-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 18F-FPEB is suitable for quantifying mGluR5 in humans. COPYRIGHT
AB - 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, 18F-3-fluoro-5-[(pyridin-3-yl)ethynyl] benzonitrile ( 18F-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 μSv/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 18F-FPEB; it showed acceptable test-retest variability of nondisplaceable binding potential (<10%) and identified the highest nondisplaceable binding potential values (from ∼.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: 18F-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 18F-FPEB is suitable for quantifying mGluR5 in humans. COPYRIGHT
KW - 3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile (FPEB)
KW - F-FPEB
KW - Human radiation dosimetry
KW - Metabotropic glutamate receptor subtype 5 (mGluR5)
KW - Neuroreceptors
KW - Positron emission tomography (PET)
KW - Radioligand
UR - http://www.scopus.com/inward/record.url?scp=84874881790&partnerID=8YFLogxK
U2 - 10.2967/jnumed.112.107995
DO - 10.2967/jnumed.112.107995
M3 - Article
C2 - 23404089
AN - SCOPUS:84874881790
SN - 0161-5505
VL - 54
SP - 388
EP - 396
JO - Journal of Nuclear Medicine
JF - Journal of Nuclear Medicine
IS - 3
ER -