NIMH DIRP Molecular Imaging Branch - Section on PET Imaging

Figure Legend: A 56-year-old HIV positive man with hypertension, normal exam, and unremarkable brain MRI enrolled in a PET study using ¹¹C-PBR28. ¹¹C-PBR28 binds to peripheral benzodiazepine receptors, which are over-expressed in brain inflammation. The PET scan showed focal increase of ¹¹C-PBR28 binding in the right basal ganglia. The patient informed us of a previously unreported, transient weakness in his left face and hand that occurred between the MRI and PET scan. Repeat MRI demonstrated a new lesion, consistent with stroke, in the right basal ganglia. PET imaging with ¹¹C-PBR28 can identify inflammation in stroke, even in very small areas of infarction.

Background: Inflammation is involved in many diseases and is commonly associated with white blood cells (called macrophages) that "eat" the destroyed tissue. In the central nervous system, these cells are called "activated microglia". A quantitative imaging measure of inflammation would help to diagnose disorders and assess the efficacy of anti-inflammatory treatments. We developed a few new radioligands that bind to a protein (PBR) that is associated with macrophages in the periphery and with activated microglia in the brain. These new radioligands appear to have much higher specific signal than an older agent developed several years ago. We tested these radioligands in a rat model of stroke, in monkeys, and finally in humans.

We reported an unusual case in which we were able to identify a stroke that presented as an incidental finding, the first time a stroke has been PET imaged in humans using the radioligand ¹¹C-PBR28 (Kreisl et al 2009) Although ¹¹C-PBR28 had never before been used to image stroke in humans, we identified an infarct, without a priori knowledge that the lesion existed. Furthermore, we found that ¹¹C-PBR28 was capable of measuring microglial activation with high sensitivity and specificity. In fact, ¹¹C-PBR28 has high enough signal-to-noise to localize inflammation to relatively small areas. Thus, it appears that ¹¹C-PBR28 can identify inflammation in stroke in humans, and may have clinical use in measuring microglial response to ischemia.

Effect of Single Nucleotide Polymorphism. We discovered that about 10% of the population has low affinity to the TSPO radioligand [¹¹C]PBR28 (Kreisl et al., 2010b; (PDF File), which was later shown to be caused by a common single nucleotide polymorphism in exon 3 of the TSPO gene. The resulting three groups are homozygous for high affinity state (HH), homozygous for low affinity state (LL), or heterozygous (HL). In a recent study, we sought to assess the utility of in vitro receptor binding to distinguish these three groups (HH, LL, and HL) and to extrapolate its impact on the sensitivity of future clinical PET studies (Kreisl et al., 2012; (PDF File)). More specifically, we sought to determine: 1) if TSPO genotype correlates with in vitro PBR28 binding using peripheral leukocytes and in vivo using brain PET imaging; 2) if differential affinity exists for PBR28 in both controls and in disease states (in this case, schizophrenia); and 3) if correcting for genotype improves the sensitivity of PBR28 to detect group differences in TSPO density measured in postmortem brain from schizophrenia subjects and healthy controls. We found that in vitro displacement assays with peripheral leukocytes accurately predicted TSPO genotype in all subjects. Thus, it appears that either leukocyte binding or genotyping can be used to accurately separate TSPO genotypes. In vivo, brain uptake of [¹¹C]PBR28 was on average 40% higher in HH than in HL subjects, but with significant overlap. In addition, TSPO binding in postmortem brain from individuals with schizophrenia was 16% higher than in control brain, an effect that was statistically significant only after correcting for TSPO genotype. Our results strongly suggest that clinical studies with [¹¹C]PBR28 will have increased statistical power and require smaller sample sizes if they incorporate the genotype of the subjects. Thus, we recommend measuring the Ala147Thr polymorphism in all future studies using [¹¹C]PBR28, as well as in other second-generation TSPO radioligands.

References:
W.C. Kreisl, G. Mbeo, M. Fujita, S.S. Zoghbi, V.W. Pike, R.B. Innis, and J.C. McArthur. Stroke incidentally identified with improved positron emission tomography for microglia activation. Arch. Neurol. 66: 1288-1289, 2009. (PDF File)

W.C. Kreisl, M. Fujita, Y. Fujimura, N. Kimura, K.J. Jenko, P. Kannan, J. Hong, C.L. Morse, S.S. Zoghbi, R.L. Gladding, S. Jacobson, U. Oh, V.W. Pike, and R.B. Innis. Comparison of [¹¹C]-(R)-PK 11195 and [¹¹C]PBR28, two radioligands for translocator protein (18 kDa) in human and monkey: implications for positron emission tomographic imaging of this inflammation biomarker. NeuroImage. 49: 2924-2932, 2010. (PDF File)

W.C. Kreisl, K.J. Jenko, C.S. Hines, C.H. Lyoo, W. Corona, C.L. Morse, S.S. Zoghbi, T. Hyde, J.E. Kleinman, V.W. Pike, F.F. McMahon, and R.B. Innis. A genetic polymorphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation. J. Cereb. Blood Flow Metab. In press. 2012. (PDF File)