Poster 14: Evaluation of Novel Radiotracers Targeting Non-Dopaminergic Striatal Biomarkers in HD: 18F-FPEB and PET Imaging for Metabotropic Glutamate Receptor Type 5 (mGluR5) Expression in Healthy Subjects and Subjects with Huntington Disease (HD)

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Objective Presented here is a first-in-human study of 3-[ 18 F]fluoro-5-(2-pyridinylethynyl)benzonitrile ( 18 F-FPEB) and PET imaging of mGluR5 in subjects with HD and healthy controls Background mGluR5 is highly expressed on enkephalinergic striatal neurons and in other neocortical structures. mGluR5 expression may be reduced because of neuron loss or alteration of gene expression. Therefore, mGluR5 may be a useful biomarker for early brain changes in HD, HD progression, or for drug development in HD. 18 F-FPEB binds mGluR5 with high affinity and specificity. Prior studies in non-human primates demonstrated 18 F-FPEB uptake consistent with the known distribution of mGluR5 expression. Methods Early HD patients ( n = 2) and healthy controls (HC, n = 2) underwent imaging. Subjects received 5 mCi 18 F-FPEB i.v. and serial dynamic PET projection data were acquired for 3 to 6 hours. Regional equilibrium tissue distribution volume measurements were assessed in striatal, neocortical, thalamic, and cerebellar regions. The standardized uptake value (SUV) ratios of targets to a cerebellar reference region were compared in HD and HC. Results Both HD subjects were female with Htt repeat expansions ≥35. HD_1: age 54 yr, UHDRS subscores motor 13 and TFC 13. HD_2: age 44 yr, UHDRS motor 6 and TFC 11. The HCs were both male, ages 57 and 43 yr. The HCs revealed intense uptake in striatal and cortical gray matter areas, moderate uptake in thalamus, and low, but not absent, uptake in cerebellum. For HCs, mean SUV ratios to cerebellum were, for anterior cingulate, 6.79; for temporal lobe, 6.15; for caudate, 5.44; and for putamen, 4.89. The HD subjects revealed a mean reduction in 18 F-FPEB uptake in striatal regions of 25–30% and temporal lobe and limbic cortical areas of 20–35%. Conclusions 18 F-FPEB is a promising PET radiotracer for evaluating mGluR5 with excellent characteristics for human imaging. This first-in-human study indicates that 18 F-FPEB PET may detect early reductions in striatal and neocortical mGluR5 in relatively mildly symptomatic HD subjects. Future studies are ongoing to evaluate these objectives and other nondopaminergic striatal markers further.