title: Synthesis and Preclinical Evaluation of 11C-UCB-J as a PET Tracer for Imaging the Synaptic Vesicle Glycoprotein 2A in the Brain.
abstract: The synaptic vesicle glycoprotein 2A (SV2A) is found in secretory vesicles in neurons and endocrine cells. PET with a selective SV2A radiotracer will allow characterization of drugs that modulate SV2A (e.g., antiepileptic drugs) and potentially could be a biomarker of synaptic density (e.g., in neurodegenerative disorders). Here we describe the synthesis and characterization of the SV2A PET radiotracer (11)C-UCB-J ((R)-1-((3-((11)C-methyl-(11)C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one) in nonhuman primates, including whole-body biodistribution.
  
  
  
  (11)C-UCB-J was prepared by C-(11)C-methylation of the 3-pyridyl trifluoroborate precursor with (11)C-methyl iodide via the Suzuki-Miyaura cross-coupling method. Rhesus macaques underwent multiple scans including coinjection with unlabeled UCB-J (17, 50, and 150 μg/kg) or preblocking with the antiepileptic drug levetiracetam at 10 and 30 mg/kg. Scans were acquired for 2 h with arterial sampling and metabolite analysis to measure the input function. Regional volume of distribution (VT) was estimated using the 1-tissue-compartment model. Target occupancy was assessed using the occupancy plot; the dissociation constant (Kd) was determined by fitting self-blocking occupancies to a 1-site model, and the maximum number of receptor binding sites (Bmax) values were derived from baseline VT and from the estimated Kd and the nondisplaceable distribution volume (VND).
  
  
  
  (11)C-UCB-J was synthesized with greater than 98% purity. (11)C-UCB-J exhibited high free fraction (0.46 ± 0.02) and metabolized at a moderate rate (39% ± 5% and 24% ± 3% parent remaining at 30 and 90 min) in plasma. In the monkey brain, (11)C-UCB-J displayed high uptake and fast kinetics. VT was high (∼25-55 mL/cm(3)) in all gray matter regions, consistent with the ubiquitous expression of SV2A. Preblocking with 10 and 30 mg/kg of levetiracetam resulted in approximately 60% and 90% occupancy, respectively. Analysis of the self-blocking scans yielded a Kd estimate of 3.4 nM and Bmax of 125-350 nM, in good agreement with the in vitro inhibition constant (Ki) of 6.3 nM and regional Bmax in humans. Whole-body biodistribution revealed that the liver and the brain are the dose-limiting organs for males and females, respectively.
  
  
  
  (11)C-UCB-J exhibited excellent characteristics as an SV2A PET radiotracer in nonhuman primates. The radiotracer is currently undergoing first-in-human evaluation.
authors: Yale PET Center, New Haven, Connecticut nabeel.nabulsi@yale.edu.
authors: Nabeel B
authors: NB
authors: Nabulsi
authors: UCB Biopharma, Braine-l'Alleud, Belgium; and.
authors: Joël
authors: J
authors: Mercier
authors: Yale PET Center, New Haven, Connecticut.
authors: Daniel
authors: D
authors: Holden
authors: UCB Biopharma, Braine-l'Alleud, Belgium; and.
authors: Stephane
authors: S
authors: Carré
authors: Yale PET Center, New Haven, Connecticut.
authors: Soheila
authors: S
authors: Najafzadeh
authors: UCB Biopharma, Braine-l'Alleud, Belgium; and.
authors: Marie-Christine
authors: MC
authors: Vandergeten
authors: Yale PET Center, New Haven, Connecticut.
authors: Shu-Fei
authors: SF
authors: Lin
authors: UCB Biopharma, Braine-l'Alleud, Belgium; and.
authors: Anand
authors: A
authors: Deo
authors: UCB Biopharma, Braine-l'Alleud, Belgium; and.
authors: Nathalie
authors: N
authors: Price
authors: UCB Biopharma, Braine-l'Alleud, Belgium; and.
authors: Martyn
authors: M
authors: Wood
authors: Yale PET Center, New Haven, Connecticut.
authors: Teresa
authors: T
authors: Lara-Jaime
authors: UCB Biopharma, Braine-l'Alleud, Belgium; and.
authors: Florian
authors: F
authors: Montel
authors: Intracellular Therapeutics, New York, New York.
authors: Marc
authors: M
authors: Laruelle
authors: Yale PET Center, New Haven, Connecticut.
authors: Richard E
authors: RE
authors: Carson
authors: UCB Biopharma, Braine-l'Alleud, Belgium; and.
authors: Jonas
authors: J
authors: Hannestad
authors: Yale PET Center, New Haven, Connecticut.
authors: Yiyun
authors: Y
authors: Huang
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D060326:Chemistry Techniques, Synthetic; D005260:Female; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D010539:Permeability; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D011854:Radiochemistry; D051381:Rats; D014018:Tissue Distribution
chemical_list: C000618323:1-((3-(methylpyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one; D008562:Membrane Glycoproteins; D011725:Pyridines; D011759:Pyrrolidines; D011760:Pyrrolidinones
keywords: 11C-UCB-J; PET; SV2A; biomarker; epilepsy; levetiracetam; nonhuman primate; rhesus monkey; synaptic vesicle glycoprotein