The Positron Emission Tomography Ligand DAA1106 Binds With High Affinity to Activated Microglia in Human Neurological Disorders

Abstract

Chronic microglial activation is an important component of many neurological disorders, and imaging activated microglia in vivo will enable the detection and improved treatment of neuroinflammation. 1-(2-Chlorphenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carbox-amide (PK11195), a peripheral benzodiazepine receptor ligand, has been used to image neuroinflammation, but the extent to which PK11195 binding distinguishes activated microglia and reactive astrocytes is unclear. Moreover, PK11195 may lack sufficient sensitivity for detecting mild neuroinflammation. We hypothesized that N-(2,5-dimethoxybenzyl)-N-(4-fluoro-2-phenoxyphenyl) acetamide (DAA1106), a new ligand that binds specifically to peripheral benzodiazepine receptor, binds to activated microglia in human neurological diseases with higher affinity than does PK11195. We therefore compared the pharmacological binding properties of [3H](R)-PK11195 and [3H]DAA1106 in postmortem tissues from patients with cerebral infarcts, amyotrophic lateral sclerosis, Alzheimer disease, frontotemporal dementia, and multiple sclerosis (n = 10 each). In all diseases, [3H]DAA1106 showed a higher binding affinity as reflected by lower dissociation constant (KD) values than that of [3H](R)-PK11195. Moreover, specific binding of both ligands correlated with the presence of activated microglia identified by immunohistochemistry in situ. We conclude that 1) ligands that bind peripheral benzodiazepine receptor mainly label activated microglia in human neurological disorders and that 2) DAA1106 may possess binding characteristics superior to those of PK11195, which may be beneficial for in vivo positron emission tomography imaging.

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

“…Although one report has speculated that PK11195 may have a low-affinity binding site (Broaddus and Bennett, 1990), the majority of literature published earlier (Doble et al, 1987;Miyazawa et al, 1998;Rao and Butterworth, 1997;Venneti et al, 2008) found evidence for only a single site. Our study supports this conclusion.…”

In Vivo Assessment of Brain White Matter Inflammation in Multiple Sclerosis with 18F-PBR111 PET

“…TSPO-targeted radioligands colocalizes with markers of activated microglia (8,11,25,26). An immunohistochemical analysis of postmortem MS brain tissue was largely consistent with these findings, suggesting that most cells expressing TSPO in acute MS lesions were macrophages or microglia (9), although it should be cautioned that antibody-based localization of the TSPO peptide and expression of the binding domain for the TSPO radioligands need not be the same.…”

Assessment of Neuroinflammation in Transferred EAE Via a Translocator Protein Ligand

“…Although [ 11 C]-(R)-PK11195 is widely used for imaging of microglia, its considerable high plasma protein binding, high levels of nonspecific binding, relatively poor blood-brain barrier permeability and short half-life, limits its use in brain imaging (Chauveau et al, 2008). Recently, alternative PET radioligands for TSPO including the phenoxyarylacetamide derivative [ 11 C]-DAA1106 and its analogues (Gulyas et al, 2009;Takano et al, 2010;Venneti et al, 2008), the imidazopyridines (PBR111) and its analogues (Boutin et al, 2007a;Fookes et al, 2008) (Boutin et al, 2007b;James et al, 2008) have been investigated.…”