Development and In Vivo Preclinical Imaging of Fluorine-18-Labeled Synaptic Vesicle Protein 2A (SV2A) PET Tracers
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Synaptic vesicle protein 2A (SV2A) serves as a biomarker of synaptic density and positron emission tomography (PET) imaging of SV2A could provide a tool to assess progression of neurodegenerative diseases. Two tracers have primarily been reported and characterized in vivo: [11C]UCB-J and [18F]UCB-H. In early human studies, [11C]UCB-J showed promising results, while its F-18-labeled analogue [18F]UCB-H showed suboptimal specific signal in comparison to [11C]UCB-J. Considering the limited use of [11C]UCB-J to facilities with a cyclotron, having a F-18 variant would facilitate large, multicenter imaging trials. We have screened several F-18 derivatives of UCB-J in non-human primates and identified a promising F-18 PET candidate, [18F]MNI-1126, with additional investigations of the racemate [18F]MNI-1038, affording a signal comparable to [11C]UCB-J.
F-18 derivatives of UCB-J and UCB-H were synthesized and administered to non-human primates for microPET imaging. Following screenings, [18F]MNI-1038 (racemate) and [18F]MNI-1126 (R-enantiomer) were identified with the highest signal and favorable kinetics and were selected for further imaging. Kinetic modeling with one- and two-tissue compartmental models, and linear methods were applied to PET data using metabolite-corrected arterial input function. Pre-block scans with levetiracetam (LEV, 10, 30 mg/kg, iv) were performed to determine the tracers’ in vivo specificity for SV2A. Two whole-body PET studies were performed with [18F]MNI-1038 in one male and one female rhesus, and radiation absorbed dose estimates and effective dose (ED, ICRP-103) were estimated with OLINDA/EXM 2.0.
All compounds screened displayed very good brain penetration, with a plasma-free fraction of ~ 40 %. [18F]MNI-1126 and [18F]MNI-1038 showed uptake and distribution the most consistent with UCB-J, while the other derivatives showed suboptimal results, with similar or lower uptake than [18F]UCB-H. VT of [18F]MNI-1126 and [18F]MNI-1038 was high in all gray matter regions (within animal averages ~ 30 ml/cm3) and highly correlated with [11C]UCB-J (r > 0.99). Pre-blocking of [18F]MNI-1126 or [18F]MNI-1038 with LEV showed robust occupancy across all gray matter regions, similar to that reported with [11C]UCB-J (~ 85 % at 30 mg/kg, ~ 65 % at 10 mg/kg). Using the centrum semiovale as a reference region, BPND of [18F]MNI-1126 reached values of up to ~ 30 to 40 % higher than those reported for [11C]UCB-J. From whole-body imaging average ED of [18F]MNI-1038 was estimated to be 22.3 μSv/MBq, with tracer being eliminated via both urinary and hepatobiliary pathways.
We have identified a F-18-labeled tracer ([18F]MNI-1126) that exhibits comparable in vivo characteristics and specificity for SV2A to [11C]UCB-J in non-human primates, which makes [18F]MNI-1126 a promising PET radiotracer for imaging SV2A in human trials.
Key wordsSV2A F-18 PET imaging Synaptic density Neurodegenerative disorders MNI-126
Compliance with Ethical Standards
This study followed protocols approved by the Yale University Institutional Animal Care and Use Committee.
Conflict of Interest
Keneth Marek and John Seibyl are Invicro equity holders. Kenneth Marek is a scientific consultant for GE Healthcare, Takeda Pharmaceuticals, Denali Therapeutics, Roche Pharma, Prothena Corp., and Lundbeck. All other authors declare that they have no conflict of interest.
- 3.Douaud M, Feve K, Pituello F, Gourichon D, Boitard S, Leguern E, Coquerelle G, Vieaud A, Batini C, Naquet R, Vignal A, Tixier-Boichard M, Pitel F (2011) Epilepsy caused by an abnormal alternative splicing with dosage effect of the SV2A gene in a chicken model. PLoS One 6:e26932CrossRefGoogle Scholar
- 4.Kaminski RM, Matagne A, Leclercq K, Gillard M, Michel P, Kenda B, Talaga P, Klitgaard H (2008) SV2A protein is a broad-spectrum anticonvulsant target: functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy. Neuropharmacology 54:715–720CrossRefGoogle Scholar
- 5.Kaminski RM, Gillard M, Klitgaard H (2012) Targeting SV2A for discovery of antiepileptic drugs. In: Jasper’s basic mechanisms of the epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US)Google Scholar
- 6.Nicolas JM, Hannestad J, Holden D, Kervyn S, Nabulsi N, Tytgat D, Huang Y, Chanteux H, Staelens L, Matagne A, Mathy FX, Mercier J, Stockis A, Carson RE, Klitgaard H (2016) Brivaracetam, a selective high-affinity synaptic vesicle protein 2A (SV2A) ligand with preclinical evidence of high brain permeability and fast onset of action. Epilepsia 57:201–209CrossRefGoogle Scholar
- 13.Bahri MA, Plenevaux A, Aerts J, Bastin C, Becker G, Mercier J, Valade A, Buchanan T, Mestdagh N, Ledoux D, Seret A, Luxen A, Salmon E (2017) Measuring brain synaptic vesicle protein 2A with positron emission tomography and [18F]UCB-H. Alzheimers Dement (N Y ) 3:481–486Google Scholar
- 14.Warnier C, Lemaire C, Becker G, Zaragoza G, Giacomelli F, Aerts J, Otabashi M, Bahri MA, Mercier J, Plenevaux A, Luxen A (2016) Enabling efficient positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) with a robust and one-step radiosynthesis of a highly potent 18F-labeled ligand ([(18)F]UCB-H). J Med Chem 59:8955–8966CrossRefGoogle Scholar
- 15.Finnema SJ, Nabulsi NB, Mercier J, et al. (2017) Kinetic evaluation and test-retest reproducibility of [11C]UCB-J, a novel radioligand for positron emission tomography imaging of synaptic vesicle glycoprotein 2A in humans. J Cereb Blood Flow Metab 271678X17724947Google Scholar
- 16.Nabulsi NB, Mercier J, Holden D, Carre S, Najafzadeh S, Vandergeten MC, Lin SF, Deo A, Price N, Wood M, Lara-Jaime T, Montel F, Laruelle M, Carson RE, Hannestad J, Huang Y (2016) Synthesis and preclinical evaluation of 11C-UCB-J as a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the brain. J Nucl Med 57:777–784CrossRefGoogle Scholar
- 19.Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, MacGregor RR, Hitzemann R, Bendriem B, Gatley SJ, Christman DR (1990) Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab 10:740–747CrossRefGoogle Scholar
- 22.(2006) Human alimentary tract model for radiological protection. ICRP Publication 100. A report of The International Commission on Radiological Protection. Ann ICRP 36:25–327, iiiGoogle Scholar
- 23.Ziessman HA, Jones DA, Muenz LR, Agarval AK (2003) Cholecystokinin cholescintigraphy: methodology and normal values using a lactose-free fatty-meal food supplement. J Nucl Med 44:1263–1266Google Scholar
- 24.Thomas SR, Stabin MG, Chen CT, Samaratunga RC (1999) MIRD Pamphlet No. 14 revised: a dynamic urinary bladder model for radiation dose calculations. Task Group of the MIRD Committee, Society of Nuclear Medicine. J Nucl Med 40:102S–123SGoogle Scholar
- 25.Stabin MG, Sparks RB, Crowe E (2005) OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med 46:1023–1027Google Scholar
- 26.(2002) Basic anatomical and physiological data for use in radiological protection: reference values. A report of age- and gender-related differences in the anatomical and physiological characteristics of reference individuals. ICRP Publication 89. Ann ICRP 32:5–265Google Scholar
- 27.(2007) The 2007 Recommendations of the International Commission on Radiological Protection. ICRP publication 103. Ann ICRP 37:1–332Google Scholar
- 28.(1991) ICRP, 1991. 1990 Recommendations of the International Commission on Radiological Protection. ICRP Publication 60. Ann ICRP 21Google Scholar