11C-DPA-713 has much greater specific binding to translocator protein 18 kDa (TSPO) in human brain than 11C-(R)-PK11195

Positron emission tomography (PET) radioligands for translocator protein 18 kDa (TSPO) are widely used to measure neuroinflammation, but controversy exists whether second-generation radioligands are superior to the prototypical agent 11C-(R)-PK11195 in human imaging. This study sought to quantitatively measure the “signal to background” ratio (assessed as binding potential (BPND)) of 11C-(R)-PK11195 compared to one of the most promising second-generation radioligands, 11C-DPA-713. Healthy subjects had dynamic PET scans and arterial blood measurements of radioligand after injection of either 11C-(R)-PK11195 (16 subjects) or 11C-DPA-713 (22 subjects). To measure the amount of specific binding, a subset of these subjects was scanned after administration of the TSPO blocking drug XBD173 (30–90 mg PO). 11C-DPA-713 showed a significant sensitivity to genotype in brain, whereas 11C-(R)-PK11195 did not. Lassen occupancy plot analysis revealed that the specific binding of 11C-DPA-713 was much greater than that of 11C-(R)-PK11195. The BPND in high-affinity binders was about 10-fold higher for 11C-DPA-713 (7.3) than for 11C-(R)-PK11195 (0.75). Although the high specific binding of 11C-DPA-713 suggests it is an ideal ligand to measure TSPO, we also found that its distribution volume increased over time, consistent with the accumulation of radiometabolites in brain.

[1]  Richard B. Banati,et al.  Positron emission tomography imaging of neuroinflammation , 2007, Neurotherapeutics.

[2]  Ronald Boellaard,et al.  Development of a Tracer Kinetic Plasma Input Model for (R)-[11C]PK11195 Brain Studies , 2005, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[3]  Masahiro Fujita,et al.  Brain and whole-body imaging in nonhuman primates of [11C]PBR28, a promising PET radioligand for peripheral benzodiazepine receptors , 2008, NeuroImage.

[4]  Sami S Zoghbi,et al.  Synthesis and evaluation in monkey of two sensitive 11C-labeled aryloxyanilide ligands for imaging brain peripheral benzodiazepine receptors in vivo. , 2008, Journal of medicinal chemistry.

[5]  R. Rupprecht,et al.  Variation in binding affinity of the novel anxiolytic XBD173 for the 18 kDa translocator protein in human brain , 2011, Synapse.

[6]  S. Hume,et al.  Synthesis of the enantiomers of [N-methyl-11C]PK 11195 and comparison of their behaviours as radioligands for PK binding sites in rats. , 1994, Nuclear medicine and biology.

[7]  R. Boellaard,et al.  Evaluation of Reference Tissue Models for the Analysis of [11C](R)-PK11195 Studies , 2006, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[8]  Roger N Gunn,et al.  Determination of [11C]PBR28 Binding Potential in vivo: A First Human TSPO Blocking Study , 2014, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[9]  S. Meikle,et al.  Synthesis and in vivo evaluation of a novel peripheral benzodiazepine receptor PET radioligand. , 2005, Bioorganic & medicinal chemistry.

[10]  R. P. Maguire,et al.  Consensus Nomenclature for in vivo Imaging of Reversibly Binding Radioligands , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[11]  Robert B. Innis,et al.  Mixed-Affinity Binding in Humans with 18-kDa Translocator Protein Ligands , 2011, The Journal of Nuclear Medicine.

[12]  S. Zoghbi,et al.  Evaluation of ultrafiltration for the free-fraction determination of single photon emission computed tomography (SPECT) radiotracers: beta-CIT, IBF, and iomazenil. , 1994, Journal of pharmaceutical sciences.

[13]  Kimberly J. Jenko,et al.  Neuroinflammation in Temporal Lobe Epilepsy Measured Using Positron Emission Tomographic Imaging of Translocator Protein. , 2015, JAMA neurology.

[14]  Jeih-San Liow,et al.  PET imaging of the dopamine transporter with 18F-FECNT: a polar radiometabolite confounds brain radioligand measurements. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[15]  Masahiro Fujita,et al.  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 , 2010, NeuroImage.

[16]  D. Nutt,et al.  Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. , 2006, Trends in pharmacological sciences.

[17]  Tetsuya Suhara,et al.  [(11)C]DAA1106: radiosynthesis and in vivo binding to peripheral benzodiazepine receptors in mouse brain. , 2003, Nuclear medicine and biology.

[18]  Mark Slifstein,et al.  Measuring Drug Occupancy in the Absence of a Reference Region: The Lassen Plot Re-Visited , 2010, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[19]  R. Boellaard,et al.  Noninvasive imaging of macrophages in rheumatoid synovitis using 11C-(R)-PK11195 and positron emission tomography. , 2008, Arthritis and rheumatism.

[20]  Roger N Gunn,et al.  Two Binding Sites for [3H]PBR28 in Human Brain: Implications for TSPO PET Imaging of Neuroinflammation , 2010, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[21]  David J. Schlyer,et al.  Graphical Analysis of Reversible Radioligand Binding from Time—Activity Measurements Applied to [N-11C-Methyl]-(−)-Cocaine PET Studies in Human Subjects , 1990, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[22]  V. Vladimirov,et al.  Translocator Protein (18 kD) as Target for Anxiolytics Without Benzodiazepine-Like Side Effects , 2009 .

[23]  André Syrota,et al.  Synthesis of N‐(11C) methyl, N‐(methyl‐1 propyl), (chloro‐2 phenyl)‐1 isoquinoleine carboxamide‐3 (PK 11195): A new ligand for peripheral benzodiazepine receptors , 1984 .

[24]  M. James,et al.  [11C]-DPA-713 and [18F]-DPA-714 as New PET Tracers for TSPO: A Comparison with [11C]-(R)-PK11195 in a Rat Model of Herpes Encephalitis , 2009, Molecular Imaging and Biology.

[25]  M. Pomper,et al.  Initial Evaluation of 11C-DPA-713, a Novel TSPO PET Ligand, in Humans , 2009, Journal of Nuclear Medicine.

[26]  Kimberly J. Jenko,et al.  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 , 2013, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.