title: Two binding sites for [3H]PBR28 in human brain: implications for TSPO PET imaging of neuroinflammation.
abstract: [(11)C]PBR28, a radioligand targeting the translocator protein (TSPO), does not produce a specific binding signal in approximately 14% of healthy volunteers. This phenomenon has not been reported for [(11)C]PK11195, another TSPO radioligand. We measured the specific binding signals with [(3)H]PK11195 and [(3)H]PBR28 in brain tissue from 22 donors. Overall, 23% of the samples did not generate a visually detectable specific autoradiographic signal with [(3)H]PBR28, although all samples showed [(3)H]PK11195 binding. There was a marked reduction in the affinity of [(3)H]PBR28 for TSPO in samples with no visible [(3)H]PBR28 autoradiographic signal (K(i)=188+/-15.6 nmol/L), relative to those showing normal signal (K(i)=3.4+/-0.5 nmol/L, P<0.001). Of this latter group, [(3)H]PBR28 bound with a two-site fit in 40% of cases, with affinities (K(i)) of 4.0+/-2.4 nmol/L (high-affinity site) and 313+/-77 nmol/L (low-affinity site). There was no difference in K(d) or B(max) for [(3)H]PK11195 in samples showing no [(3)H]PBR28 autoradiographic signal relative to those showing normal [(3)H]PBR28 autoradiographic signal. [(3)H]PK11195 bound with a single site for all samples. The existence of three different binding patterns with PBR28 (high-affinity binding (46%), low-affinity binding (23%), and two-site binding (31%)) suggests that a reduction in [(11)C]PBR28 binding may not be interpreted simply as a reduction in TSPO density. The functional significance of differences in binding characteristics warrants further investigation.
authors.affiliation: Department of Experimental Medicine and Toxicology, Imperial College London, Hammersmith Hospital, London, UK. d.owen@imperial.ac.uk
authors.forename: David R
authors.initials: DR
authors.lastname: Owen
authors.forename: Owain W
authors.initials: OW
authors.lastname: Howell
authors.forename: Sac-Pham
authors.initials: SP
authors.lastname: Tang
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Wells
authors.forename: Idriss
authors.initials: I
authors.lastname: Bennacef
authors.forename: Mats
authors.initials: M
authors.lastname: Bergstrom
authors.forename: Roger N
authors.initials: RN
authors.lastname: Gunn
authors.forename: Eugenii A
authors.initials: EA
authors.lastname: Rabiner
authors.forename: Martin R
authors.initials: MR
authors.lastname: Wilkins
authors.forename: Richard
authors.initials: R
authors.lastname: Reynolds
authors.forename: Paul M
authors.initials: PM
authors.lastname: Matthews
authors.forename: Christine A
authors.initials: CA
authors.lastname: Parker
mesh_terms: D000081:Acetamides / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001345:Autoradiography; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000000981:diagnostic imaging*; D001923:Brain Chemistry; D002250:Carbon Radioisotopes; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007546:Isoquinolines; D008297:Male; D008566:Membranes / Q000000981:diagnostic imaging / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism; D009443:Neuritis / Q000000981:diagnostic imaging*; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000378:metabolism*; D011869:Radioligand Assay; D018079:Receptors, GABA / Q000378:metabolism*; D014015:Tissue Banks
chemical_list: D000081:Acetamides; D002250:Carbon Radioisotopes; D007546:Isoquinolines; C526798:N-(2-methoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide; D009419:Nerve Tissue Proteins; D011725:Pyridines; D018079:Receptors, GABA; C499229:TSPO protein, human; C037850:PK 11195