First-in-Human Assessment of the Novel PDE2A PET Radiotracer 18F-PF-05270430.
This was a first-in-human study of the novel phosphodiesterase-2A (PDE2A) PET ligand (18)F-PF-05270430. The primary goals were to determine the appropriate tracer kinetic model to quantify brain uptake and to examine the within-subject test-retest variability.



In advance of human studies, radiation dosimetry was determined in nonhuman primates. Six healthy male subjects participated in a test-retest protocol with dynamic scans and metabolite-corrected input functions. Nine brain regions of interest were studied, including the striatum, white matter, neocortical regions, and cerebellum. Multiple modeling methods were applied to calculate volume of distribution (VT) and binding potentials relative to the nondisplaceable tracer in tissue (BPND), concentration of tracer in plasma (BPP), and free tracer in tissue (BPF). The cerebellum was selected as a reference region to calculate binding potentials.



The dosimetry study provided an effective dose of less than 0.30 mSv/MBq, with the gallbladder as the critical organ; the human target dose was 185 MBq. There were no adverse events or clinically detectable pharmacologic effects reported. Tracer uptake was highest in the striatum, followed by neocortical regions and white matter, and lowest in the cerebellum. Regional time-activity curves were well fit by multilinear analysis-1, and a 70-min scan duration was sufficient to quantify VT and the binding potentials. BPND, with mean values ranging from 0.3 to 0.8, showed the best intrasubject and intersubject variability and reliability. Test-retest variability in the whole brain (excluding the cerebellum) of VT, BPND, and BPP were 8%, 16%, and 17%, respectively.



(18)F-PF-05270430 shows promise as a PDE2A PET ligand, albeit with low binding potential values.
Department of Radiology and Biomedical Imaging, PET Center, Yale School of Medicine, New Haven, Connecticut; and mika.naganawa@yale.edu.
Mika
M
Naganawa
Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
Rikki N
RN
Waterhouse
Department of Radiology and Biomedical Imaging, PET Center, Yale School of Medicine, New Haven, Connecticut; and.
Nabeel
N
Nabulsi
Department of Radiology and Biomedical Imaging, PET Center, Yale School of Medicine, New Haven, Connecticut; and.
Shu-Fei
SF
Lin
Department of Radiology and Biomedical Imaging, PET Center, Yale School of Medicine, New Haven, Connecticut; and.
David
D
Labaree
Department of Radiology and Biomedical Imaging, PET Center, Yale School of Medicine, New Haven, Connecticut; and.
Jim
J
Ropchan
Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
Sanela
S
Tarabar
Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
Nicholas
N
DeMartinis
Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
Adam
A
Ogden
Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
Anindita
A
Banerjee
Department of Radiology and Biomedical Imaging, PET Center, Yale School of Medicine, New Haven, Connecticut; and.
Yiyun
Y
Huang
Department of Radiology and Biomedical Imaging, PET Center, Yale School of Medicine, New Haven, Connecticut; and.
Richard E
RE
Carson
D000818:Animals; D053961:Azabicyclo Compounds / Q000097:blood / Q000493:pharmacokinetics*; D001384:Azetidines / Q000097:blood / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D003198:Computer Simulation; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000378:metabolism*; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007553:Isotope Labeling; D008253:Macaca mulatta; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D057054:Molecular Imaging / Q000379:methods; D009928:Organ Specificity; D010865:Pilot Projects; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000097:blood / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution
C582922:4-(3-fluoroazetidin-1-yl)-7-methyl-5-(1-methyl-5-(4-(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)imidazo(5,1-f)(1,2,4)triazine; D053961:Azabicyclo Compounds; D001384:Azetidines; D019275:Radiopharmaceuticals; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; C517275:PDE2A protein, human
brain imaging; dosimetry; phosphodiesterase 2A; positron emission tomography; test-retest reproducibility