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A comparison of the high‐affinity peripheral benzodiazepine receptor ligands DAA1106 and ( R )‐PK11195 in rat models of neuroinflammation: implications for PET imaging of microglial activation
Author(s) -
Venneti Sriram,
Lopresti Brian J.,
Wang Guoji,
Slagel Susan L.,
Mason N. Scott,
Mathis Chester A.,
Fischer Michelle L.,
Larsen Niccole J.,
Mortimer Amanda D.,
Hastings Teresa G.,
Smith Amanda D.,
Zigmond Michael J.,
Suhara Tetsuya,
Higuchi Makoto,
Wiley Clayton A.
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04690.x
Subject(s) - microglia , in vivo , neuroinflammation , translocator protein , ex vivo , binding potential , positron emission tomography , receptor , chemistry , ligand (biochemistry) , pathology , pharmacology , medicine , neuroscience , biology , biochemistry , inflammation , microbiology and biotechnology , disease
Activated microglia are an important feature of many neurological diseases and can be imaged in vivo using 1‐(2‐chlorophenyl)‐ N ‐methyl‐ N ‐(1‐methylpropyl)‐3‐isoquinolinecarboxamide (PK11195), a ligand that binds the peripheral benzodiazepine receptor (PBR). N ‐(2,5‐dimethoxybenzyl)‐ N ‐(5‐fluoro‐2‐phenoxyphenyl) acetamide (DAA1106) is a new PBR‐specific ligand that has been reported to bind to PBR with higher affinity compared with PK11195. We hypothesized that this high‐affinity binding of DAA1106 to PBR will enable better delineation of microglia in vivo using positron emission tomography. [ 3 H]DAA1106 showed higher binding affinity compared with [ 3 H]( R )‐PK11195 in brain tissue derived from normal rats and the rats injected intrastriatally with 6‐hydroxydopamine or lipopolysaccharide at the site of the lesion. Immunohistochemistry combined with autoradiography in brain tissues as well as correlation analyses showed that increased [ 3 H]DAA1106 binding corresponded mainly to activated microglia. Finally, ex vivo autoradiography and positron emission tomography imaging in vivo showed greater retention of [ 11 C]DAA1106 compared with [ 11 C]( R )‐PK11195 in animals injected with either lipopolysaccaride or 6‐hydroxydopamine at the site of lesion. These results indicate that DAA1106 binds with higher affinity to microglia in rat models of neuroinflammation when compared with PK11195, suggesting that [ 11 C]DAA1106 may represent a significant improvement over [ 11 C]( R )‐PK11195 for in vivo imaging of activated microglia in human neuroinflammatory disorders.