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Molecular Imaging Branch (MIB)

1.7 Radiotracers for PBR

1 Ligand Development

1.7 Radiotracers for PBR

The so-called ‘peripheral benzodiazepine receptor’ (PBR) has structure, function, pharmacology and distribution that are unrelated to those of central benzodiazepine receptors (CBR).94 PBR primarily reside on the outer mitochondrial membrane of microglia and astrocytes. They are of interest for imaging in brain because their concentrations are elevated in response to various insults, including stroke, tumors and neurodegenerative disorders. For over two decades the isoquinoline carboxamide, [11C]PK 11195 (20), originally as racemate and later as its homochiral (R)-enantiomer,95 has been the standard PET radiotracer for imaging brain PBR. However, this radiotracer has major limitations, including poor entry to normal brain, due to high lipophilicity plus Pgp substrate behavior, and extensive poorly understood metabolism with possible entry of radioactive metabolites into brain. Recently, aryloxyanilides96 have been described as high affinity ligands for PBR. These ligands have attracted interest by our group and others97,98,99 for the development of improved PET radiotracers for PBR. We identified three target radiotracers for synthesis and study.100,101,102,103 One of these, [11C]PBR28102 (IC50, 0.6 nM; cLogP, 2.98; 19), has now advanced to eIND approval, while two others, [18F]PBR06 (IC50, 0.2 nM; cLogP, 4.20; 12) and [11C]PBR01 (IC50, 64 pM; cLogP, 4.26; 58) are also promising.