Initial Evaluation of 11C-DPA-713, a Novel TSPO PET Ligand, in Humans

Microglia are the resident macrophages of the central nervous system (CNS), responsible for phagocytosis of cellular debris, antigen presentation, and a multitude of other functions in the CNS (1). Once exposed to neuronal injury, microglial cells become activated, with resultant phenotypic transformation from a ramified to an enlarged amoeboid morphology (2). When activated, microglia demonstrate increased expression of translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor (PBR) (3), which is an 18-kDa protein localized primarily to the outer mitochondrial membrane (4) of many cells. In the normal brain, TSPO expression has been described in endothelial and smooth muscle cells, subpial glia, intravascular monocytes, and ependymal cells (5). In view of the increased TSPO expression associated with activated microglia and macrophages in states of disease (5,6), TSPO is considered a marker of the neuroinflammatory burden. Microglial activation is suspected in playing a role in the pathophysiology of multiple CNS diseases. Therefore, a reliable imaging biomarker for microglial activation could prove useful in better characterizing those diseases noninvasively. Unlike anatomic imaging techniques such as CT and MRI, functional imaging techniques, namely PET, can image microglial activation through the use of radioactively labeled ligands that bind to TSPO. The prototype of such radioligands is 11C-R-PK11195, a lipid-soluble isoquinoline carboxamide, with the R-enantiomer having higher affinity for TSPO than the S-enantiomer (7). Despite being used extensively in the imaging of multiple CNS disease entities, 11C-R-PK11195 suffers from many limitations including high nonspecific binding, high plasma protein binding, low brain uptake (8), and the lack of a universally validated compartmental model to describe the kinetic behavior in the brain across different pathologies (9–12). Those limitations have instigated the search for alternative TSPO binding radioligands with more favorable characteristics such as higher affinity, lower nonspecific binding, lower protein binding, and higher brain uptake. Numerous TSPO PET ligands have been developed in the last several years (13), including 11C-DAA1106 (14) and 11C-PBR28 (15). Recently, a pyrazolopyrimidine, 11C-N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-acetamide (11C-DPA-713), has been described (8,16). In animal studies, 11C-DPA-713, compared with 11C-R-PK11195, demonstrated higher affinity for TSPO (Ki = 4.7 vs. 9.3 nM). 11C-DPA-713 is also less lipophilic (logP = 2.4) than 11C-R-PK11195 (logP = 3.4) (16), suggesting that 11C-DPA-713 should exhibit less nonspecific binding in the brain and lower binding to plasma proteins. The high specificity of 11C-DPA-713 binding in vivo was demonstrated in a primate via the potent blockade of brain uptake when PK11195 was delivered before 11C-DPA-713 (16). That study also showed that flumazenil had no blocking effect; thus, 11C-DPA-713 binds exclusively to TSPO and not central benzodiazepine receptors (16). Studies in a rat model of neurodegeneration have shown 11C-DPA-713 to have greater specificity in discriminating between normal and lesioned brain than 11C-R-PK11195 (17). As a first step to study its potential for clinical use, we examined the cerebral uptake of 11C-DPA-713 in healthy human control subjects and compared its pharmacokinetics with those of 11C-R-PK11195.