Introduction
Criteria for evaluating CNS PET tracers and outcome parameters
Ability to accumulate within the CNS
Suitable pharmacokinetics and selectivity
Common outcome parameters
Outcome parameter | Full name | Equation | Description |
---|---|---|---|
%ID | Percentage injected dose | \( \frac{\%\mathrm{of}\ \mathrm{injected}\ \mathrm{dose}}{\mathrm{g}\ \mathrm{of}\ \mathrm{tissue}} \) | Percentage of injected radiotracer per unit volume (or weight) of tissue |
SUV | Standardised uptake value | \( \frac{\%\mathrm{ID}\times 100}{\mathrm{subject}\ \mathrm{weight}} \) | Weight corrected parameter of %ID |
SUVr | Relative SUV | \( \frac{{\mathrm{SUV}}_{\mathrm{target}}}{{\mathrm{SUV}}_{\mathrm{other}}} \) | Ratio between SUV values between target and other regions |
VT | Volume of distribution | \( \frac{C_{\mathrm{T}}}{C_{\mathrm{P}}} \) | Ratio of tracer concentration between tissue and plasma at equilibrium |
DVR | Distribution volume ratio | \( \frac{V_{\mathrm{T}\ \left(\mathrm{tissue}\right)}}{V_{\mathrm{T}\ \left(\mathrm{ND}\right)}} \) | Ratio of VT between tissue and non-displaceable tissue component (often given by reference region when available) |
BPND | Binding potential non-displaceable | \( \frac{V_{\mathrm{T}\ \left(\mathrm{tissue}\right)}}{V_{\mathrm{T}\ \left(\mathrm{ND}\right)}}-1 \) | Normalised DVR; when VT (tissue) = VT (ND), BPND = 0 |
RO | Receptor occupancy | \( \frac{{\mathrm{BP}}_{\mathrm{ND}\ \left(\mathrm{baseline}\right)}-{\mathrm{BP}}_{\mathrm{ND}\ \left(\mathrm{drug}\right)}}{{\mathrm{BP}}_{\mathrm{ND}\ \left(\mathrm{baseline}\right)}}\times 100\% \) | % of receptors occupied, usually by drug administration |
TRV | Test-retest value | \( \left|\frac{{\mathrm{OP}}_{\mathrm{test}}-{\mathrm{OP}}_{\mathrm{retest}}}{\left({\mathrm{OP}}_{\mathrm{test}}+{\mathrm{OP}}_{\mathrm{retest}}\right)/2}\right|\times 100\% \) | Average variation of OP from two scans on the same subject without intervention |
COV | Coefficient of variance | \( \frac{\mathrm{SD}}{\mathrm{Mean}}\times 100\% \) | Average variation of OP within a group |
ICC | Intraclass correlation coefficient | \( \frac{\mathrm{BSMSS}-\mathrm{WSMSS}}{\mathrm{BSMSS}+\left(K-1\right)\times \mathrm{WSMSS}} \) | Comparison of reliability of within-subject variability to between-subject variability |
TRV Test retest value AD Alzheimer’s disease ALS Amyotrophic lateral sclerosis A2A Adenosine 2A α7-nAChR α-7 subtype of the nicotinic acetylcholine receptor BBB Blood-brain barrier Bmax Target density BPND Binding potential (non-displaceable) cAMP Cyclic adenosine monophosphate CBD Corticobasal degeneration cGMP Cyclic guanosine monophosphate CN Cognitively normal CNS Central nervous system COV Coefficient of variance COX Cyclooxygenase DLB Dementia with Lewy bodies DVR Distribution volume ratio FAAH Fatty acid amide hydrolase FDA Food and Drugs Administration GABA γ-aminobutyric acid GBq Gigabecquerel HChealthy controls HD Huntington’s disease ICC Intraclass correlation coefficient I2BS Imidazoline 2 subtype binding site KO Knockout LBD Lewy body disorders M Molar MAO Monoamine oxygenase MCI Mild cognitive impairment mGluR Metabotropic glutamate receptor MRI Magnetic resonance imaging MS Multiple sclerosis NFT Neurofibrillary tangles NHP Non-human primate OLR Opioid-like receptor OR Opioid receptor PD Parkinson’s disease PDE Cyclic nucleotide phosphodiesterase PET Positron emission tomography PSP Progressive supranuclear palsy RO Receptor occupancy SPECT Single-photon emission computed tomography SRTM Simplified reference tissue model SUV Standardised uptake value SUVr Relative standardised uptake value SV2A Synaptic vesicle glycoprotein 2A TCM Tissue compartment model TDP-43 TAR DNA-binding protein TRPV1 Vanilloid receptor TSPO Translocator protein VAChT Vesicular acetylcholine transporter VT Volume of distribution Κ-OR Kappa opioid receptor 5-HT Serotonin %ID Percentage injected dose |
Methods
Search strategy
Evaluation criteria
Review format
Targets for proteinopathies
Tau imaging
Tracer | First in human | In vivo homologous block (parameter, species) | In vivo heterologous block | Human TRV | Inter-subject variability outcome: value (regions) | Reference region | Highest uptake AD (parameter, region) | Uptake HC (parameter, region) | Advantages | Limitations |
---|---|---|---|---|---|---|---|---|---|---|
18F-AV-1451 | 2013 [21] | −45% (VT, healthy NHP) [22] | N/A | <10% [23] | ICC, >0.90 [23] | Cerebellum [24] | 2.2 (SUVR, inferior temporal/cerebellum) [25] | 1.2 (SUVR, inferior temporal/cerebellum) [25] | ||
18F-THK523 | 2014 [39] | N/A | N/A | N/A | N/A | Cerebellum (not validated) [39] | 1.9 (SUVR, subcortical white matter/cerebellar cortex) [40] | 1.6 (SUVR, subcortical white matter/cerebellar cortex) [40] | Significant difference in AD compared with that in HC [40]. | |
18F-THK5117 | 2015 [42] | N/A | N/A | N/A | N/A | Cerebellum (not validated) [43] | 1.3 (SUVR, neocortex/cerebellar grey matter) [42] | 1.1 (SUVR, neocortex/cerebellar grey matter) [42] | Limited selectivity data available. High white matter binding [42]. Replaced by later derivatives. | |
18F-THK5317 | 2016 [45] | N/A | N/A | <10% [46] | ICC, >0.85 (isocortical and subcortical), 0.52 (posterior cingulate cortex) [46] | Cerebellum [45] | 1.4 (SUVR, limbic region/cerebellar grey matter) [46] | 1.2 (SUVR limbic region/cerebellar grey matter) [46] | Significant alterations between AD and HC and significant correlation to cognitive scores [46]. Low TRV. | Limited selectivity data available. |
18F-THK5351 | 2016 [47] | N/A | −37–52% (MAO inhibitor, MCI and AD) [48] | N/A | N/A | Cerebellum (not validated) [49] | 3.0 (SUVR, hippocampus/cerebellar cortex) [47] | 2.1 (SUVR, hippocampus/cerebellar cortex) [47] | ||
18F-MK-6240 | 2018 [55] | N/A | Ongoing | ICC, >0.95 [57] | Cerebellum [57] | 3.8 (SUVR, precuneus/cerebellar grey matter) [57] | 1.1 (SUVR, precuneus/cerebellar grey matter) [57] | |||
18F-RO-948 | 2018 [58] | N/A | N/A | <10% [58] | ICC, >0.90 [59] | Cerebellum [59] | 2.8 (SUVR, inferior parietal lobe/cerebellar cortex) [59] | 1.4 (SUVR, inferior parietal lobe/cerebellar cortex) [59] | Fast metabolism in human [58]. Limited selectivity data available. Structural derivative of 18F-AV-1451 so may suffer similar drawbacks. | |
18F-MNI-815 | 2015 (CT) [60] | N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A | Replaced by 18F-PI2620 in Primal Imaging’s clinical trials. |
18F-GTP-1 | 2016 (CA) [61] | N/A | N/A | Ongoing | N/A | Cerebellum (not validated) [61] | N/A | N/A | Reported correlation to cognitive scores [61]. | No peer-reviewed in vivo data available. |
18F-AM-PBB3 | 2017 (CA) [62] | N/A | N/A | N/A | N/A | N/A | N/A | N/A | Lower binding in basal ganglia and thalamus than 11C-PBB-3 parent tracer [62]. | Off-target binding in choroid plexus [62]. No peer-reviewed in vivo data available. |
18F-PM-PBB3 | 2017 (CA) [62] | N/A | N/A | Ongoing | N/A | N/A | N/A | N/A | Lower binding in basal ganglia and thalamus than 11C-PBB-3 parent tracer [62]. | Off-target binding in choroid plexus [62]. No peer-reviewed in vivo data available. |
18F-PI2620 | 2018 (CT) [63] | N/A | N/A | N/A | N/A | N/A | N/A | N/A | Low affinity to MAO-A and B via competition assay [64]. | No peer-reviewed in vivo data available. |
Selectivity studies for tau agents
In vivo
In vitro
Pharmacokinetic profiles of tau tracers
Conclusions and outstanding issues for tau imaging
Tau has multiple targets
In-depth characterisation of tracers pre-clinically
Lack of selective compounds
Receptor, transporter, and synaptic targets
System | Target | Tracer | First in human | In vivo homologous block (parameter, species) | In vivo heterologous block (parameter, species) | Human TRV | Interpatient variability outcome: value (regions) | Highest uptake (parameter, region) | Reference region | Advantages | Limitations |
---|---|---|---|---|---|---|---|---|---|---|---|
Cholinergic | VAChT | 18F-FEOBV | 2014 [65] | −28% (SUVr, rat) [66] | N/A | Ongoing | COV, 20% (striatum) 6–12% (cortical) [65] | 25 (BPND, striatum) [65] | Cerebellar grey matter [65] | ||
18F-VAT | 2018 (CA) [68] | N/A | −90% (SUVr-1, NHP [non-selective block]) [69]; −54% (VT, NHP [non-selective block]) [70] | N/A | N/A | N/A | N/A | Heterologous blocking agent also binds to sigma binding sites.[71] No in-human data published. | |||
α7-nAChR | 18F-ASEM | 2014 [72] | 40% (RO, NHP) [73] | ≈−90% (%ID, rat), ≈−80% (VT, NHP) [74] | 11.7±9.8% [75]; 10.8±5.1% [72] | COV, 21.1–27.2% [72] | 22 mL/cm3 (VT, putamen) [72] | None available | Target has no reference region. | ||
Adenosine | A2A | 18F-MNI-444 | 2015 [76] | 100–103% (striatal RO, NHP) [77] | 95% (striatal RO, NHP) [77] | <10% on average [76] | COV, 12.2–25.0% (basal ganglia structures) [76] | 3.3 mL/cm3 (VT, Putamen) [76] | Cerebellum [76] | Small bias with using cerebellum as reference region [76]. Moderately long scan times may be necessary. | |
Synaptic vesicle proteins | SV2A | 18F-UCB-H | 2015 [78] | N/A | −44% (VT, whole brain, rat), [79] | N/A | COV, 12.2% (whole brain) [78] | 7.8 mL/cm3 (VT, gyrus rectus) [80] | None available | 18F allows greater availability than 11C. | Lower sensitivity and BPND compared with 11C-UCB-J [81]. Target has no reference region. |
11C-UCB-J | 2016 [82] | −75% (VT, NHP) [83] | −78% (VT, NHP) [83] | <10% [84] | ICC, typically >0.6 [84] | 23 mL/cm3 (VT, centrum semiovale) [81] | None available | Target has no reference region. | |||
Imidazoline receptors | I2BS | 11C-BU99008 | 2018 [85] | N/A | 5–25% [85] | COV, 17.6–31.1% (subcortical structures) [85] | 106 mL/cm3 (VT, striatum) [85] | None available | Areas of high TRV and COV, slow kinetics, long scan times required [85]. Target has no reference region. | ||
Metabotropic glutamate receptors | mGluR1 | 11C-ITMM | 2013 [88] | −85% (SUV, rat) [89] | −85% (SUV, rat) [89] | N/A | 2.6 mL/cm3 (VT, cerebellar cortex) [88] | White matter (not validated) [93] | Relatively low brain uptake, slow kinetics [88]. No validated reference region. | ||
18F-FIMX | 2016 [94] | −85% (SUV, NHP) [95] | ≈−100% (displacement SUVr, NHP) [95] | Ongoing | COV, 9.4–13.2% [94] | 11 mL/cm3 (VT, cerebellum) [94] | N/A | Fast metabolism in human [95]. No validated reference region. | |||
Opioid | κ | 11C-GR103545 | 2014 [96] | Not suitable due to toxicity. [97] | −75% (VT, human [non-selective block]) [96] | 8–41% [96] | ICC, 0.81±0.08 [96] | 28 mL/cm3 (VT, amygdala) [96] | None available | Highest affinity for κ in vitro [96]. | No suitable reference region. Slow kinetics, high TRV in amygdala, low injectable mass tolerance [96]. |
11C-LY2795050 | 2014 [98] | −60% (DVR, NHP) [99] | ≤10% [101] | ICC, >0.8 (all reported regions except amygdala), 0.56 (amygdala) [101] | 4.0 mL/cm3 (VT, amygdala) [100] | None available | |||||
Serotonin | 5-HT2 | 11C-Cimbi-36 | 2014 [103] | N/A | <10% on average [105] | ICC, 0.72–0.91 (all reported regions except subsequent), 0.24-0.32 (anterior and posterior cingulate and striatum) [105] | 40 mL/cm3 (VT, medial inferior temporal gyrus) [103] | Cerebellum (negative bias) [103] | |||
Purinoceptor | P2X7 | 18F-JNJ-64413739 | 2018 [106] | 93% occupancy (HC) [106] | N/A | 10.7±2.2% [106] | ICC, >0.90 (2TCM) [106] | 3.3 mL/cm3 (VT, brainstem) [106] | None available | First P2X7 tracer published in man. Successful occupancy study conducted [106]. | Relatively high COV (33.5±2.2%) [106]. No characterisation with structurally dissimilar block. No suitable reference region. |
11C-SMW139 | 2018 (CT) | N/A | ≈−100% (SUVr-1, rat viral vector model) [107] | N/A | N/A | N/A | N/A | Good response to block in rodent model [107]. | Limited data available. High non-parent metabolite in rodent brain [107] | ||
11C-JNJ-54173717 | 2018 (CA) [108] | ≈−100% (SUVr-1, rat viral vector model) [109] | ≈−65% (SUV, NHP) [109] | N/A | N/A | N/A | N/A | Good response to block in rodent model and in NHP [109]. | Limited data available, higher baseline signal in non-hP2X7 areas, possibility of off-target binding [109]. | ||
11C-GSK1482160 | 2018 (CA) [110] | ≈−60% (VT, mouse lipopolysaccharide model) [111] | N/A | N/A | N/A | N/A | N/A | No characterisation with structurally dissimilar block, slow kinetics, low brain uptake [112] |
Cholinergic targets
Selectivity data for cholinergic tracers
Pharmacokinetic properties of cholinergic tracers
Conclusions and outstanding issues for recent cholinergic tracers
Adenosine A2A
Selectivity data of 18F-MNI-444
Pharmacokinetic properties of 18F-MNI-444
Conclusions and outstanding issues for 18F-MNI-444
Synaptic vesicle glycoprotein
Selectivity data for SV2A tracers
Pharmacokinetic profile of SV2A tracers
Conclusions and outstanding issues for SV2A tracers
Imidazoline 2 binding site
Selectivity data for 11C-BU99008
Pharmacokinetic profile of 11C-BU99008
Conclusions and outstanding issues for I2BS imaging
Metabotropic glutamate receptor 1
Selectivity data for mGluR1 tracers
Pharmacokinetic profile of mGluR1 tracers
Conclusions and outstanding issues for mGluR1 tracers
κ opioid receptor
Selectivity data for κ-OR tracers
Pharmacokinetic profile of κ-OR tracers
Conclusions and outstanding issues for κ-OR tracers
Serotonin 5-HT2R
Selectivity data for 11C-Cimbi-36
Pharmacokinetic profile of 11C-Cimbi-36
Conclusions and outstanding issues for 11C-Cimbi-36
P2X7
Selectivity data for P2X7 tracers
Pharmacokinetic profile of P2X7 tracers
Conclusions and outstanding issues for P2X7 tracers
Enzymatic targets
Family | Target | Tracer | First in human | In vivo homologous block (parameter, species) | In vivo heterologous block (parameter, species) | Human TRV | Interpatient variability outcome: value (regions) | Highest uptake (parameter, region) | Reference region | Advantages | Limitations |
---|---|---|---|---|---|---|---|---|---|---|---|
Cox | Cox-1 | 11C-PS13 | 2018 (CA) [113] | −57% (VT, NHP) [114] | −55% (VT, NHP) [114] | Ongoing | N/A | N/A | N/A | Relatively good response by heterogeneous and homogeneous block, selectivity for COX-1 over COX-2 shown in vivo [114]. Only COX-1 tracer translated into man. | Limited data available. Low plasma free fraction and relatively high non-displaceable binding in NHP brain [114]. |
Mitochondrial complexes | MC1 | 18F-BCPP-EF | 2018 (CA) [115] | N/A | N/A | N/A | 28 mL/cm3 (VT, striatum) [115] | N/A | |||
Histone deacetylases | HDAC 1-3 | 11C-Martinostat | 2016 [122] | −35% (% uptake normalised to uptake at 6 min, rat) [123] | <10% [122] | COV, 11–19% [122] | 18 mL/cm3 (VT, cerebellum) [122] | N/A | No reference region available. Slow kinetics, higher interpatient variability using VT measurements.[122] | ||
Phosphodiesterases | PDE2 | 18F-PF-05270430 | 2016 [126] | 32% decrease in striatal VT (NHP) [127] | N/A | ≤10% [126] | ICC, 0.66–0.90 (all reported regions except putamen), 0.23 (putamen) [126] | 1.3 mL/cm3 (VT, putamen) [126] | Cerebellum (not validated) [126] | Only in-human PDE2 tracer. Low TRV. | |
PDE10A | 18F-JNJ42259152 | 2013 [128] | −89% (SUVr-1, rat) [129] | ≈−100% (SUVr-1, KO mouse) [129] | <10% on average[130] | ICC, >0.85 [130] | 1.0 mL/cm3 (VT, putamen) [130] | Frontal cortex [130] | |||
18F-MNI-654 | 2014 [132] | N/A | N/A | 20% [132] | N/A | 4.5 mL/cm3 (VT, striatum) [132] | Cerebellum [132] | High VT and BPND in humans [132]. | Deemed inferior to 18F-MNI659 due to higher TRV, lower uptake and slower kinetics [132]. | ||
18F-MNI-659 | 2014 [132] | N/A | −47% (VT, human) [133] | <10% [132] | ICC, >0.80 [132] | 2.8 mL/cm3 (VT, globus pallidus) [132] | Cerebellum [132] | Lack of pre-clinical in vivo selectivity data published. | |||
11C-IMA-107 | 2014 [136] | ≈−100% (SUVr-1, pig) [136] | −67% (VT, NHP) [136] | 12% [137] | COV, <10% (89 of 91 regions) [137] | 2.2 (BPND, putamen) [138] | Cerebellum [137] | Lower BPND than other PDE10A tracers [136]. | |||
11C-Lu AE92686 | 2014 [140] | −94% (VT, NHP) [141] | 82% (RO, NHP) [140] | <10% [140] | COV, <20% [140] | 6.5 (BPND, putamen) [142] | Cerebellum [140] | ||||
11C-T-773 | 2016 [143] | −80% (VT, NHP) [144] | −47% (VT, NHP) [145] | <10% [143] | ICC, >0.85 [143] | 5.5 mL/cm3 (VT, putamen) [144] | None available | High brain penetration [143]. Low TRV. | |||
Fatty acid amide hydrolase | FAAH | 11C-CURB (URB694) | 2013 [146] | −86% (SUV, Rat) [147] | >−90% (λk3, human) [148] | <10% on average[148] | ICC, 0.55–0.89 [148] | 0.17 mL/cm3 (λk3, thalamus) [146] | None available | ||
11C-MK-3168 | 2018 [150] | ≈−50% (SUV, NHP) [151] | >−90% (VT, humans) [150] | <12% [152] | N/A | 29 mL/cm3 (VT, undefined) [150] | None available |