Two Binding Sites for [3H]PBR28 in Human Brain: Implications for TSPO PET Imaging of Neuroinflammation

• Published in: Journal of cerebral blood flow and metabolism Vol. 30; no. 9; pp. 1608 - 1618
• Main Authors: Owen, David R, Howell, Owain W, Tang, Sac-Pham, Wells, Lisa A, Bennacef, Idriss, Bergstrom, Mats, Gunn, Roger N, Rabiner, Eugenii A, Wilkins, Martin R, Reynolds, Richard, Matthews, Paul M, Parker, Christine A
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.09.2010; Nature Publishing Group; Sage Publications Ltd
• Subjects: Acetamides - metabolism; Adult; Aged; Aged, 80 and over; Autoradiography; Binding Sites; Binding, Competitive - drug effects; Biological and medical sciences; Brain - diagnostic imaging; Brain Chemistry; Carbon Radioisotopes; Female; Humans; Immunohistochemistry; Investigative techniques, diagnostic techniques (general aspects); Isoquinolines; Male; Medical sciences; Membranes - diagnostic imaging; Membranes - metabolism; Middle Aged; Nerve Tissue Proteins - analysis; Nerve Tissue Proteins - metabolism; Nervous system; Neuritis - diagnostic imaging; Neurology; Original; Positron-Emission Tomography; Pyridines - metabolism; Radioligand Assay; Receptors, GABA - metabolism; Tissue Banks; Ultrasonic investigative techniques; Vascular diseases and vascular malformations of the nervous system; [3H]PBR28; PBR; radioligand binding; TSPO; [3H]PK11195; Human; Nervous system diseases; H]PBR28; Cerebral disorder; Encephalon; Central nervous system disease; H]PK11195; [; Positron emission tomography; Cerebrovascular disease
• ISSN: 0271-678X; 1559-7016
• DOI: 10.1038/jcbfm.2010.63

[11C]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 [11C]PK11195, another TSPO radioligand. We measured the specific binding signals with [3H]PK11195 and [3H]PBR28 in brain tissue from 22 donors. Overall, 23% of the samples did not generate a visually detectable specific autoradiographic signal with [3H]PBR28, although all samples showed [3H]PK11195 binding. There was a marked reduction in the affinity of [3H]PBR28 for TSPO in samples with no visible [3H]PBR28 autoradiographic signal (Ki=188±15.6 nmol/L), relative to those showing normal signal (Ki=3.4±0.5 nmol/L, P<0.001). Of this latter group, [3H]PBR28 bound with a two-site fit in 40% of cases, with affinities (Ki) of 4.0±2.4 nmol/L (high-affinity site) and 313±77 nmol/L (low-affinity site). There was no difference in Kd or Bmax for [3H]PK11195 in samples showing no [3H]PBR28 autoradiographic signal relative to those showing normal [3H]PBR28 autoradiographic signal. [3H]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 [11C]PBR28 binding may not be interpreted simply as a reduction in TSPO density. The functional significance of differences in binding characteristics warrants further investigation.