JS PD KB

PET, Imaging, and Tracer Development

32 min read

PET, Imaging, and Tracer Development

This topic page reorganises the 18 source notes filed under pet-imaging (16) and microglia-imaging (2) into reading-order axes. It does not replace the by-photo Markdown; every substantive claim links back to a source note or the canonical transcription. Where a source carries Uncertain Spans, that uncertainty is preserved here rather than smoothed out.

Authoring Boundary And Source Selection

The corpus carries imaging evidence in many places — MC1 PET / 31P MRS / [3H]BCPP-EF on the mitochondria pages, MJFF MC1 PET in Parkin-PD planning and DATSCAN / 18F-DOPA / neuromelanin-MRI on the Parkin pages, TSPO / DPA714 / FEPPA tracer comparison and Microglial Imaging on the inflammation pages, and DAT / [18F]AV-133 / SV2A / σ1R PET / Amydis retinal-tracer on the biomarkers-outcomes pages. This topic does not re-state that material; it links across to the existing sibling topics where the imaging modality is the biomarker for that mechanism. The 18 sources covered here are the ones that the section heuristic placed in sections/pet-imaging (first nav_path entry rooted in a PET / imaging / tracer-discovery nav cluster) plus the two sources in sections/microglia-imaging (Microglial Imaging nav root, TSPO rs6971 polymorphism page and its Modelling / NHP / PDE continuation). All 18 are disjoint from the source sets covered by parkin, mitochondria, inflammation, and biomarkers-outcomes.

A consequence of the heuristic is that several pages whose visible body is the NLRP3 inhibitor program’s PET tracer chemistry / in-vivo work, or whose body is unrelated to PET (psychiatric outcomes slides, lysosomotropic vs LAMP1-binder lysosomal-tracer block, rare- disease prevalence) sit here because their first nav_path entry is PE, PET, NHP, Pipeline, or Terminology > Psychosis in PD > pipeline > Radiochemical. Those pages are anchored on the topic but are not paraphrased; the canonical body lives on the by-photo page.

Overview

The corpus treats PET / imaging as eight overlapping problems. (1) A PET tracer parameters / outcome-parameters reference framework (Bmax, Kd, Bmax/Kd binding potential, %ID, SUV, V_T, BP_ND, R1/k2, TRV / COV / ICC, dosimetry, specific activity, microdosing) anchored on Patel-Gibson 2008, Friden 2014, Honer 2014, McCluskey 2020, Hostetler 2016, Kazami 2019, and Takeda’s PETSC slide deck (20240722_184809, 20240722_184813, 20240722_184823). (2) PET Steering Committee (PETSC) workflow / lead optimization assay flow / Discovery Process to FIH Study slides (20240722_184816, 20240722_184819). (3) The Selectivity / cold-tracer LC-MS triage / Preclinical study / Clinical study workflow stack (20240722_184826, 20240722_184829). (4) Regulatory Development Path PET ligand (Mosessian 2014; eIND vs traditional IND requirements; microdosing study definition; glossary; AAV PET; safety; sharefolder; synthesis timeline) (20240722_184836). (5) NLRP3 PET tracer chemistry and in-vivo workstream — [3H]TR-126, TR06647850, TR06683014/15, TR06616126, TR06692993, TR06693098, TR06800430, MCC950 — as it sits in the pet-imaging section through its PE / PET / NHP first nav-roots (20240722_183252, 20240722_183258, 20240722_183301). (6) VMAT-2 PET / [18F]AV-133 — Schwarz 2019 NS imaging strategy, Cristian Salina 2022 sample-size analysis, AV-133 baseline-scan inventory (20240722_184604). (7) 7T MRI sequence taxonomy and PD-relevant 7T literature (20240722_184153). (8) Microglial Imaging axis — TSPO rs6971 polymorphism (Mizrahi 2012, Lee 2022), Takeda subject genotype list, NBB case TSPO-class inventory, Dartmouth / Havrda IRB / tracer planning, NHP/PDE planning grid (20240722_183247, 20240722_183250). Three off-axis pages — the Radiochemical glossary (20240722_184420), the Lysosomotropic vs LAMP1-binder lysosomal-tracer block (20240722_184424), and the PSYCHIATRIC OUTCOMES IN PD PPMI slide block (20240722_184427) — sit in this section because of their first nav_path entry rather than because the visible body is PET / imaging.

Source Coverage

The 18 sources sit across 13 first-level nav_path clusters. The topic axes below collapse those clusters as follows:

nav root (first nav_path entry)sourcescovered axis
[MOLECULAR BIOLOGY]3Tracer parameters reference / Biomarker stage gates / Regulatory development path
PET2NLRP3-program in-vivo workflow / PSYCHIATRIC OUTCOMES PPMI slide block
Microglial Imaging2TSPO rs6971 polymorphism + NBB inventory / Modelling / NHP / PDE
7T MRI1MRI sequence taxonomy / Hyperintensity / DBM / 7T-PD literature
[PHARMACOLOGY]1PETSC workflow flowcharts (target validation, GCSi, PET Tracer Discovery)
Dose of PET tracer1Selectivity / HDAC6 cold tracer / LC-MS triage / Bavarostat workflow
NHP1NLRP3-program LPS-rat / NOMID / PS19 / ARG-postmortem-AD / [Thaw cycle] / PK
Parameters of PET ligand1Lead-optimization assay flow / PETSC slide / Discovery Process to FIH / dose tables
PE1NLRP3-program PE schedule / Chemistry PET candidate progress
PET Steering Committee1Preclinical study / In-vivo blocking PET / Clinical study examples
Pipeline1Rare-disease prevalence / Lysosomotropic vs LAMP1 / Postmortem GBA-PD lysosomal evidence
PK-PD relationship1BPND / VT comparison / Variability metrics / Bmax viability table
Terminology1Psychosis-in-PD pipeline / Radiochemical glossary / unit conversion / Rare disease
VMAT Vesicular monoamine transporter-21AAV-GT trial table tail / VMAT2 PET [18F]AV-133 / Schwarz / Cristian Salina sample-size

For exact nav_path strings and headings see pet-imaging, microglia-imaging, and the by-nav indexes listed in related_topics_by_nav.

Across the 18 sources, the source-note frontmatter records 66 uncertain_span_count entries and 0 body-embedded figure assets. The zero-figure-embed count reflects the 2026-04-29 body-purity decision (docs/decisions/2026-04-29-body-purity-and-figure-only-embeds.md): the PET / imaging pages embed Takeda PETSC slide screenshots, Bmax saturation curves, Hostetler 2016 PDE10A NHP brain panels, the Patel-Gibson 2008 Table 1 reproduction, the Friden 2014 pie charts, NHP brain coronal sections, [18F]MNI-1054 fused PET/MR images, occupancy fit plots, the Strebl 2017 Bavarostat sagittal sections, the Kroth 2019 Aβ tracer brain sections, the LC-MS cold-tracer workflow slide, the Schwarz NS imaging strategy bar charts, the Cristian Salina power-vs-effect-size curves, the Niethammer 2017 AAV2-GAD UPDRS line plot, the (Strebl, 2017 #475) Bavarostat workflow, the chemical-structure crops for HDAC6 candidate compounds and NLRP3 PET tracer chemistry, and the four PPMI slide-as-image PSYCHIATRIC OUTCOMES tables, all inside crops that also carry transcribable text (slide titles, axis labels, table headers, surrounding cell text) and so are kept as evidence rather than embedded. The 66 uncertain spans are retained as review targets and not resolved here.

Tracer Parameters And Outcome-Parameters Reference Framework

20240722_184809 is the core PET tracer parameters reference page. It covers Bmax assessment in rats (HDAC6 KO rat brain-slice protocol with [3H]T-3789533 saturation curves and the WT/KO equation pair), the Honer 2014 target-with-lowest-Bmax PET reference (extrastriatal D2 receptor pool, Bmax of 1 nM), the Bmax-to-molarity conversion (50 mg of protein per gram of tissue, 100 fmol/mg protein → 5 nM), the species comparison Summary of Bmax and Kd value table (Rat striatum / cerebrum, Monkey striatum / caudate, Human striatum at [3H]T-3789533 and MeNz columns), the Kd (흔히 Ki로 대치됨) panel (Capotosti 2022 α-syn aggregate tracer Kd 8-30 nM in tissue slices vs Mathis “1 nM or lower sweet spot”; Olsson 2004 [18F]FLB-457 in-vitro 20 pM vs in-vivo 0.27-0.43 nM), the Bmax/Kd binding potential block (Matthews 2012 practical range 0.5-15; Honer 2014 ratio of 3 minimum and >10 ideal; Takeda minimum acceptance Bmax/Kd ≥ 1), the Patel-Gibson 2008 Table 1 reproduction (DAT / D₂ / CB1 / m-AChR / m-GluR5 row-by-row Bmax, Kd, Bmax/Kd, and in-vivo Sp/Ns columns; specific cell values and footnote superscripts are flagged uncertain on the source and not re-quoted here), the Friden 2014 functional vs non-functional 47-tracer pie charts, the test-retest variability references (Ogden 2007 / Hirvonen 2008; 5-HT transporter HV ~15%; DAT in NHP ≤ 20%), the dosimetry / safety / specific-activity (>67.6 Ci/mmol) blocks, the Outcome parameters table (%ID, SUV, VT) with the Van de Bittner ≥1.0 %ID/cc threshold, the Suridjan 2019 VT < 0.2 lower bound, and the SB 확인 방법들 checklist. 6 Uncertain Spans (Summary table column-group label MeNz reading, Bmax-targets row-to-rating mapping, Patel-Gibson footnote superscripts, test-retest NHP-row alignment, Dosimetry trailing fragment, SUV equation bracket nesting) sit on the source.

20240722_184813 extends the framework with the BP_ND vs VT comparison table (BP_ND = f_NS · Bmax / KD = (VT - VND) / VND, ≥2:1 (BPND >1) criterion; FEPPA arterial-sample VT vs DPA714 reference-region SRTM BPND), the occupancy formula Occ(%) = 100 × (BPND_baseline - BPND_drug) / BPND_baseline, the Variability sub-table (TRV / COV / ICC with the McCluskey 2020 thresholds <10%, <10%,

0.8), the Hostetler 2016 PDE10A NHP-brain section illustration (non-displaceable binding via THPP-1 co-incubation; CPu, Ctx, Acb, GP, Cb, Bs, SN, Thal, Hipp anatomical labels), the Quantify target expression (Bmax) across species viability table (rodent / NHP / human Bmax for Targets 1-3 mapped to PET tracer tractability ratings), the R1 / BP_ND / k2 reference (Chauveau 2009 R1 > 1 facilitated entry), and the closing PET Tracer Viability criteria table (Kd < 10 nM, Bmax/Kd ≥ 10, LogD < 3, MDR/BCRP < 2, parent-tracer-dominant brain metabolism, tracer-dose safety). It also opens the From McCluskey 2020 — Basic description of common outcome parameters used in PET imaging studies table (%ID, SUV, Relative SUV, VT) that continues onto 20240722_184816. 5 Uncertain Spans (vertical row-label column structure, 이건 tracer 아니라 약의 성질 아닌가? annotation, Hostetler figure labels, injection 이라는데? parenthetical, McCluskey table tail on the next page) sit on the source.

20240722_184823 carries the Biomarker Types and Stage Gates — Alignment with Asset Milestones Takeda slide block (Asset timeline TE → PS → LGE → PE → CN → CS → EDE → IND → EPOC paired with the Biomarker timeline BPS → BFA → BTV → BCS TE,PD,DR → BCS PS; the four icon callouts TE / PD / DR / PS; the BPS / BFA / BTV / BCS deliverables for white-paper rationale, reagent compatibility, sensitivity / specificity / reproducibility, and in-vivo calibration), the Biomarker type-specific definition of milestones matrix (Common / Molecular Biomarker / PET ligand / Neurocircuitry rows crossed with the four BMx milestones), the Comparison: in vitro vs in vivo reference table, and the start of the Preclinical study reference block (Ashley AD postmortem [11C]NCGG401, Au-Griem- Krey 2019 [3H]GHB Jove protocol, AC Immune α-Syn PET ACI-3710 5 µM self-blocking, SPAL human postmortem, Kroth 2019 Aβ tracer Brakk I/III/V brain sections, Hostetler 2016 NHP n=4 / human n=3 region panel, Hall 1998 / Pan 2016 / Martin-Cora 2004 / Strebl 2017 / Perry 1999 / Farkas 2012 / Bannon 2002 reference rows). 5 Uncertain Spans sit on the source. The Biomarker Stage Gates rationale here is the canonical anchor for BPS / BFA / BTV / BCS as they appear elsewhere in the corpus (e.g. on biomarkers-outcomes the BAF / BAQ / BCS Biomarker Validation Milestones arc on 20240722_184726).

PET Steering Committee, Workflow, And Lead Optimization

20240722_184816 is the PETSC slide-bundle page. It carries the tail of the TRV / COV / ICC table from 184813, the Assay flow and criteria in lead optimization checklist (Compound synthesis → In vitro assays [IC50<20 nM, >50× selectivity, LogD<2.5, MDR1 ratio<2.5] → Brain PK [fub>5%, Kp>0.5, brain amide <50% relative to unchanged] → Further profiling [monkey CSF PK, target occupancy with KO mice and CN pretreatment, metabolite ID] → Radiochemistry development → Preclinical PET study), the Dose of PET tracer table (raclopride / a high-affinity brain ligand (Kd 0.1 nM) / HDAC6 / 11C CFT / Paul McQuade rows mapping species × dose × activity × receptor-occupancy <1-5%), the PET Ligand Development Steering Committee (PETSC) member roster, and two Discovery Process to Achieve PET Tracer FIH Study color-coded process flows. 3 Uncertain Spans. Specific dose-table activity values (MBq, mCi, µCi) and the receptor-occupancy column anchor are table-primary on the source page.

20240722_184819 is the [PHARMACOLOGY] > Parameters of PET ligand > Dose of PET tracer > PET Steering Committee > Workflow page containing the multi-slide workflow flowcharts: Target validation workflow, Assay flow for 1st set of PET tracer candidates, Tentative flow for GCSi - Flow of PET tracer development (preclinical), Work Flow for PET Tracer Discovery, and the PET Ligand Development Work Flow - Reviewed by PET Steering Committee (PETSC). 4 Uncertain Spans. The flowcharts are slide-style figures whose surrounding crop contains decision-box labels and arrow text, so the figure body is preserved as evidence and not embedded; the per-step decision text should be read on the source page rather than re-quoted here.

20240722_184826 is the Dose of PET tracer > PET Steering Committee > Workflow > Preclinical study page that carries (a) a continuation of the multi-page brain-section reference table (Hall 1998 whole-hemisphere human, Pan 2016, Martin-Cora 2004 saturation-binding curve, Strebl 2017 Bavarostat HDAC6, Perry 1999 [3H]EB hippocampal-region binding in nonsmokers vs smokers, Farkas 2012, Bannon 2002), (b) the Selectivity and PET probe discovery for HDAC6 (Cont'd) slide (T-4035187 / T-4055455 candidate compounds with chemical structures, IC50 / IDAC6 IC50 / HDAC1 / HDAC8 panels, KO-mouse validation bar chart, Competition with T-412 panel), (c) the Which was better to evaluate specific binding: Kp.hippocampus or Hippocampus concentration four-panel occupancy / concentration scatter plots (T-412 dose-response in HDAC6 WT / KO with per-cohort mean ± SD / CV / n cells preserved on the source page), (d) the Non-imaging methods to triage selected compounds and assess specific target binding section with the LC-MS quantification of cold-tracer tissue distribution slide (Step 1-4 mouse-to-LC-MS workflow with FLB-457 D2/D3 cerebellum / striatum / frontal cortex bar chart from ACS Chem Neurosci 2014 5:1154), the Flow/criteria of PET tracer development (cold study) three-step decision flow (criteria IC50<10 nM, Bmax/Kd>10, MDR1 ratio<3, LogD: 1-3, fu.brain>1% free [>5% preferable], Mouse IV: rapid elimination, Labeling position: 11C, 18F), (e) the Bavarostat (Strebl 2017 #475) Step 1-4 mouse workflow and (f) the Traditional vs Novel Testing Scheme for PET Tracer Discovery two-column comparison flowchart (Radioligand vs LC-MS approaches). 5 Uncertain Spans.

20240722_184829 is the PET Steering Committee > Workflow > Preclinical study > Clinical study page. The Preclinical study block compares Baseline scan (radioligand only; Brain penetrability, Regional distribution deliverables) against Blocking (pretreatment) scan (radioligand + two-dose drug candidate, two animals each; Target occupancy and plasma-exposure / target-occupancy quantitative relationship as deliverables); the example column names Takeda HDAC6 [18F]EKZ-001 ([18F]Bavarostat, 2020 cELEN), with the (fig5) note that EKZ-317 achieves higher target occupancy than ACY-775 (full HDAC6 occupancy at 2 mg/kg, >90% at 0.1 mg/kg). The page also carries (a) the In vivo PET imaging to assess regional distribution and blocking by drug candidate slide for [18F]MNI-1054 (chemical structure, fused MRI/PET axial+coronal heatmap, Selected TACs time-activity curves across Occipital lobe / Frontal lobe / Amygdala / Insula / Caudate Nucleus / Putamen / Cerebellar lobes / Pons; baseline-scan-in-NHP yellow highlight; correlation between plasma drug levels and target occupancy), (b) the second blocking-PET slide pairing Compound 1 and Compound 2 plasma-concentration vs target-occupancy fit plots (per-compound slope and Occ50 cells preserved on the source page), (c) the Clinical study Logic / Principle plot (plasma-conc-vs-Occ%, gray therapeutic-range band; bullets Test-retest reproducibility, Time course for target interaction in CNS can be different from pharmacokinetics, Phase 1 MAD에서 환자 cohort 써서 할 수 있겠군. (cf: 2상에서는 confirm dose 함), Target occupancy = O = Cfree plasma / (Cfree plasma + KD)), and (d) the start of the [18F]EKZ-001 / Bavarostat 2020 Koole open-label phase 1 study summary (cohorts A, B, C). 4 Uncertain Spans.

Regulatory Development Path PET Ligand

20240722_184836 is the [MOLECULAR BIOLOGY] > [PET] > Regulatory Development Path PET ligand page (Mosessian 2014 #2 reference). It carries the eIND / FIH vs (Traditional) IND requirements table (Microdosing P0 with Not Intended for diagnostic or therapeutic, clinical protocol, USP 823 / CFR 212 manufacturing, dosimetry in rodents, non-GLP single-species toxicology with day1 / day14 necropsy, no safety pharmacology, no genotoxicity vs the more demanding Traditional IND with GLP two-species toxicology / safety pharmacology / genotoxicity), the Microdosing study definition (not more than either 100 µg or 1/100 of estimated pharmacologically effective dose), the Outcome of PET radioligand study block (BP - which is proportional to specific binding divided by free radioligand concentration), the Glossary / Database PET / AAV PET / Safety of PET tracer / Sharefolder of Imaging / Synthesis sub-headings, and the Timeline and Process to Conduct Human TO PET Study Gantt-style flowchart (Site selection / Suitability assessment / Scale-up production of precursor and reference standard / CMC Data Package / Pre-clinical contracting / GMP radiochemistry development and validation runs / Final site qualification and CMC approval / Clinical contracting for TO PET study, with a lower row Pre-clinical validation of PET tracer as fit-for-purpose / Clinical contracting for tracer validation, plus a colour-coded legend Site selection-material-radiochemistry-prep / Contracting / In vivo PET imaging / Tracer toxicology / Protocol development and regulatory approval). 4 Uncertain Spans.

NLRP3 PET Tracer Chemistry And In-Vivo Workstream

The three PE / PET / NHP first-nav-root pages whose visible body is the NLRP3 inhibitor program’s PET tracer development workstream sit in this section because the heuristic uses the first nav_path entry. They are not paraphrased into the nlrp3-inhibitor program entity page (whose source set excludes them) and not paraphrased into inflammation (whose source set excludes them). Specific tracer IDs, dose schedules, and result cells are table-primary on the source pages.

20240722_183252 is the PE > PET > Chemistry PET page. The PE Items / Schedule block records the AQB1 (11/12 Nov), TMQB (16/17 Nov), NSRB (1/2 Dec), PRC1 (16 Dec) pivotal-meeting cadence and the Working document_PRC_Narrative_NLRP3_Sep22.docx reference. The Chemistry PET table contrasts the in-vitro Bmax desired profile (Ki <5 nM, high Fu brain >5%, specific activity >67.6 Ci/mmol) against the in-vivo profile (good PK, brain uptake and elimination, Ki and Fub, MDR1 (A>B*/ER): - (<6)), then walks across multi-iteration date-stamped rows (20210805 RSLT — TR126 Kd 16-17nM per 20220707_CNS01365_report; binding-assay Bmax of NLRP3 in insect cells over-expressing NLRP3 from [3H]-TR06616126 120 min reaction ≈ 65 pmol/mg protein → ~3.2 nM; 20220325 — Ki measurement at TSD with 1-2 month precursor synthesis + 1-2 month tritiation; 2022 — TR493 four-related-compound shipment to Novandi; the difficulty-of-methylation note; 20221012 — TR06780135 IC50 1.1 nM (h), Fu brain 1% (r); 20230111 — [3H]Compounds for in vitro Bmax measurement slide preserving MCC-950 / TR06616126 / TR06706493 / TR06780135 chemical structures as evidence; Yamatake) Anyway, our first step is ARG study of patient using TR493; Candidates for in vivo PET study 20230212 slide for TR06647850 / TR06683015 / TR0676285? / TR06683014). The Sharefold for PET URL is preserved verbatim. The Progress table records the 20210701 / 20210830 / 20210923 Marianthi (Will measure Bmax (before PE, at INVICRO LONDON, Ashley guide)) / 20211006(?) Tomimatsu / 20221209 PRC RUMENT (2nd Bmax phase 1 STUDY: ARG, [3H]PBR28 for TSPO binding, in 6OHDA Rat striatum) iterations. 5 Uncertain Spans (TR126 Kd numeral, IC50 decimal, Hit verb, 2nd Bmax phase 1 superscript, Sharefold link GUID).

20240722_183258 is the PET first-nav-root page that carries the [TSPO PET] AAV-aSyn rat plan (Sortwell protocol amendment, MSU contract amendment, IACUC approval Dec가능tjd), the 20230726 / 20230911 / 20240208 / 20240408 NLRP3 PET program timeline (FEPPA / DPA714 ready at Dana Farber; TSPO longitudinal 3-week observation; PET study 202312 surgery 20231211 + scanning schedule D1 dpa714 / D3 FEPPA / D7 dpa714 / D14 FEPPA / D21 dpa714; PE2I → result 202401(?); Parra 2020 #2452 [NLRP3 PET] 6OHDA rat C-11 labeling at Dana Farber; [18F]DPA714 7 days post surgery confered the greatest signal window), the 1st-imaging schedule (4/15/2024 surgery → 4/18/2024 ship to TBOS → 4/23/2024 1st imaging on 5 rats; weekly euthanasia rows through 7/9/2024 with day-counters 19/26/33/40/47/54/61/68/75/82/89), the [study 2: Tx impact] rodent-vs-human DPA / FEPPA defluorination note, the GOF mouse / 6OHDA Rat / LPS (systemic) Rat experimental tables (TR06692993 blocker, TR06647850 IV tracer; PO 30 mg/kg → 1h Cmax → tracer IV → 4h tissue collection; brain-surgery BBB-penetration caveat; significant blocking not observed in the vehicle-vs-993 fold-change comparison; LPS tracer (850) 0.1 & 1 mpk initial, 0.01 & 0.1 mpk second iteration, 2 → 0.5 mpk LPS dose, 1 & 2 → 2 & 4 h tissue collection; TR06683014 / TR06683015 IV in 4-day 0.5 mpk LPS rats). 5 Uncertain Spans (1st-imaging weeks-post-surgey 1.7-week initial, 6OHDA NLRP3 WB bar-chart figure, LPS Kp tail clip, confered misspelling, comp und / meli / ult / li / 3 left-edge labels).

20240722_183301 is the NHP > PDE > PE > PET page that continues the LPS-rat result table (5-fold increase of NLRP3 expression in striatum of LPS injected rat models, IL-1b 1.5-fold upregulated of 0.5 mg/kg LPS but no increase in 2 mg/kg, no TH loss, comparable to that in 6OHDA rat model, remains will be shipped to Ashley for ARG study), Interpretation/Next-step rows, the LPS (brain injection) Rat sub-table (Tissue collection 3 d, 5 d, [3H]TR-126 80 nM high SB in SF9 NLRP3 over-expressing cells but did not increase on LPS-injection side, [3H]PBR28 binding increased on the ipsilateral side of injection, in 3-day vs 5-day LPS rats), the Other models (NOMID mice / PS19 mice NLRP3-level analysis 2-11 months by August), the ARG Postmortem-AD block ([3H]MCC950 30 nM 60-75% Inhibition in Tris and Ion buffer, AD vs HC 비교는 무의미, Tracer는 MCC950만 사용, [PD & AD]: At 13nM (~Ki) no usable binding, At 80nM SB window increased using [3H]TR-126 compared to [3H]MCC950 in human tissue), the PET activities sharefolder (Study lists_NLRP3 PET.xlsx), the Scenario matrix (1st / worst e1 / worst e2 cells across Problem / Human brain ARG / In vitro / Non-imaging triaging (LC-MS) / Animal PET study / Risk columns), the [Thaw cycle] block (Snap freezing → homogenation: Ok, Fresh → homogenation → freezing: ↓ but only in 6OHDA model), and the PK readout sub-table (TR06693098 free fraction plasma/brain 0.035/0.045, T1/2 600 mg/kg group, no Day1 vs Day3 accumulation). 1 Uncertain Span (Scenario animal PET cell My disease NHP model likely No).

VMAT-2 PET / [18F]AV-133

20240722_184604 is the VMAT Vesicular monoamine transporter-2 > VMAT PET > [18F]AV-133 page. It opens with the tail of the wide AAV gene-therapy trial table (AAV2-GAD with the Niethammer 2017 #1572 sample-size note, VY-AADC02 (Voyager) NBIb-1817 P2 RESTORE-1 with the 20201114 MRI abnormalities → FDA clinical hold → 202102 termination, hAADC Jichi medical univ P1/2 dose-escalation, AXO-Lenti-PD (OXB-102, Axovant) ProSavin three-enzyme AADC + TH + GTP-cyclohydrolase P1/2, NINDS-AAV2-GDNF P1 dose-escalation, and AAV2-GDNF AskBio P1b two- cohort early-vs-late-stage PD putamen-targeted bilateral image- guided delivery; per-trial sample-size, primary/secondary endpoint, and UPDRS / DATSCAN cells are preserved on the source page rather than re-quoted here). It then carries the Yuhan 유한 MC1 / Retina / Denali / NHP spreading model / Axon DTI / lysosome biomarker matrix; the VMAT Vesicular monoamine transporter-2 Korean-language description; the [18F]AV-133 enumerated notes (Invicro distribution to the north-east USA and northern California; Adam 20200923 / 20210129 PPMI add-on longitudinal-scan plan); the 20190403 Schwarz NS imaging strategy slide (50% slowing of dopamine signal decrease over 12 months framing; per-tracer sample-size cells N=345 vs N=133 preserved on the source; three Signal-change-over-12-month bar charts comparing DaTscan vs [18F]AV-133); and the 20220622 Cristian Salina sample-size analysis (Mean % change AV-133 SBR vs Ioflupane DAT at 1Yr / 2Yr; Striatum n=30; per-cell Mean / SD / Signal-to-noise / Power=0.8 sample-size at 50% and 25% effect cells preserved on the source page; the operator-flagged I think there is a typo in this slide … it should say 450 not 45 annotation on the lower-right cell is preserved verbatim and not reconciled); the per-tracer power-vs- effect-size curves at 1y / 2y; and the AV-133 Original / Early-PD baseline-scan inventory continuing onto 20240722_184620. 2 Uncertain Spans (Cristian Salina lower-right cell 45 typo flag; trial-table 11-column structure). The DAT / [18F]AV-133 effect-size material here is the canonical anchor for the DaTscan vs [18F]AV-133 Cohen’s-d and sample-size cells on 20240722_184306 under biomarkers-outcomes; that page is not re-quoted here.

7T MRI

20240722_184153 is the 7T MRI page. The body is a Wikipedia-style MRI sequence taxonomy table covering Inversion recovery (SWI, STIR, FLAIR, DIR), Diffusion weighted (DWI / ADC / DTI), Perfusion weighted (DSC / ASL), Functional MRI (DCE / BOLD), and Magnetic resonance angiography (TOF / PC-MRA). It is followed by Hyperintensity (=T2 hyperintensity) definition / synonyms / region / cause / interpretation / disease block, the DBM (Deformation-Based Morphometry) definition, the 7T MRI 1.5T / 3T / 7T comparison table (higher SNR / spatial resolution / contrast, fMRI / MRS / volumetric MRI 좋아짐, neuromelanin MRI and DTI 도움, the cons list of skull-base sensitivity and SAR limits, the In-PD literature row pointing to van der Kolka 2013, Cho et al [45], Bajaj et al [46], Oh et al [47] for substantia-nigra subregion delineation and iron content), and the >70 7T scanners worldwide (Huber 2018) install-base note. The closing block is the Repetition Time (TR) / Time to Echo (TE) definitions and the T1 / T2 / FLAIR sequence comparison table for CSF / WM / cortex / Fat. 3 Uncertain Spans (MRI sequences table top-edge header crop, Hyperintensity citation [7], 7T MRI 1.5T column empty cells).

Microglial Imaging And TSPO

20240722_183247 is the Microglial Imaging first-nav-root page in microglia-imaging. It carries the TSPO rs6971 polymorphism background (GRCh38.p13 chr 22 NC_000022.11:g.43162920 A>G, exon 4 of the TSPO gene; protein-level amino acid substitution Ala147Thr; T [ACG] > A [GCG] missense; allele frequency A 20-30%, G 70-80%; Mizrahi 2012 #2154 TaqMan assay C_2512465_20), the DNA / Protein / express ... mapping table (A/A → Ala/Ala = HAB high-affinity binder; A/G → Ala/Thr = MAB mixed-affinity binder; G/G → Thr/Thr = LAB low-affinity binder), the population-distribution table (HAB European 9.8% / Asian 0.1% / Latin American 2.5% / African 3.6%; MAB 43.0 / 7.3 / 26.6 / 30.7%; LAB 47.2 / 92.5 / 70.9 / 65.7%), the Lee 2022 #2155 TSPO exon-4 PCR / Sanger sequencing note (mouse TSPO is 96% homologous to the rat TSPO; HapMap American 69.2% HAB, European 45.7%), the Takeda Subject ID / Genotype / Allele table (19 rows: 6 HC plus 13 PD; binder distribution LAB 1, MAB 10, HAB 8 — though the LAB-row count is for HC group and the LAB / MAB / HAB summary mini- table at the lower-left lists 1 / 10 / 8 which is preserved verbatim and flagged as image-primary on the source), the NBB Case ID / Diagnosis / TSPO polymorphism table (color-coded HAB red, MAB unmarked, LAB yellow <mark>), and the Structure section listing Seltzer (radiologist who runs the scans) and Mathew Havrda (lab guy handling IRB / blood prep / blood tests), with the Dartmouth / Tracer / Population / Timeline / Assay / BM / Protocol planning notes (tracer: i) company for synthesis → transport to Dartmouth ii) no cyclotrone? so no 11C, but 18F (or longer) iii) human tissue data (off-target check?); Population: all comer vs selection; Timeline: if 1-2 scan/w → 6 month for recruitment; BM: ASC spec? Gasdermin D?). 3 Uncertain Spans (Takeda ID row 2014-030 0/0 A/A HAB label; left-edge 092 cell prefix; LAB / MAB / HAB summary mini-table left-most letters partly cropped). The TSPO axis here connects to the inflammation topic’s Imaging neuroinflammation > DPA714 > 3rd Generation TSPO block on inflammation, the NLRP3 inhibitor program’s Microglial Imaging > NHP > PDE > PE > PET Bmax / Invicro / 6OHDA-rat / [3H]MCC950 / [3H]TR06616126 / [3H]PBR28 NHP imaging summary table on 20240722_183255, and the Microglial-Imaging cohort-evaluation table on 20240722_183244; that material is not re-stated here.

20240722_183250 is the Microglial Imaging > Modelling > NHP > PDE continuation. It carries (a) a Brain-Microglia Scenario sub-table (Plasma NLRP3 / Brain NLRP3 / Brain Microglia / cell-content / Statistical method columns with continuous-vs-binary cut-point combinations; the Korean-language 각각 고민해야 겠네 Statistical-method placeholder for every row; the SZ Aβ42 / Aβ40 reference row Brain Amyloid PET +/- (a threshold of florβpir SUVr = 1.11 to a cortical summary region normalized by the whole cerebellum reference region [11-13]) / AUC), (b) a Modelling sharepoint link (NLRP3 Inflammasome > QS M&S > Slides-Hamid), (c) an NHP / mouse / Rat planning grid (Support Biodistribution OK for small molecule, IVC → human dose prediction empty, Confidence literature empty, Human disease prediction pathology magnitude / DA characterization, NLRP3 pathway characterization empty, Timeline mouse 1m observation needed / NHP Characterization → 4m observation, Quality China issue? mouse OK if non-GLP study), and (d) the PDE Sharefolder Devyani section with the long bullet list of meeting notes, the Meeting with PRC office over PDE-rough notes January 10 2023 narrative-guidance block, the PRC office member roster (Head Global Product & Launch Strategy / Head Global Clinical Operations / Head Global Portfolio Strategy / Head R&D Strategy & External Innovation / Head Pharmaceutical Sciences / Head Global Regulatory Affairs Oncology / Head Preclinical and Translational Sciences / Head Drug Safety & Evaluation / Head Quantitative Clinical Pharmacology / Internal rotating member), and the 20221215 / 20230104 minute entries with the Working_document_PRC_Narrative_NLRP3_Sep22.docx SharePoint URL. 1 Uncertain Span (Brain Microglia row continuous 갰지 may read 같지).

Adjacent Pages Filed By Heuristic

The three off-axis pages here sit in sections/pet-imaging because of their first nav_path entry; the visible body is not PET / imaging.

20240722_184420 (Terminology > Psychosis in PD > pipeline > Radiochemical) is the Psychosis-in-PD pipeline + Radiochemical glossary page. The Psychosis-in-PD pipeline mini-table records Nuplazid (pimavanserin) by Acadia as an inverse agonist / antagonist at serotonin 5-HT2A (Ki 0.087 nM) and 5-HT2C (Ki 0.44 nM) approved by the FDA for hallucinations and delusions in PD psychosis, with the SAPS-H+D custom scale note. The Radiochemical block is the unit-conversion glossary (radioactivity / specific activity / tSIS / CPM / Efficiency / DPM / fmol/mg concentration / molarity columns) with the 1 Ci = 2.22 × 10^12 dpm / 2,220,000 dpm = 1 µCi / 33P-γ-ATP 3000 Ci/mmol / 100 fmol/mg protein → 5 nM (brain conversion factor) reference set; the [3H]MCC950 Ki 11nM vs Kd 92.63nM disagreement is preserved as written. The Definitions sub-table covers Radioactive decay, Half life, Curie / µCi, Becquerel / Bq, dpm, Specific activity, Theoretical maximum specific activity, radioactive concentration / mCi/mL or µCi/mL, Molar concentration, the PerkinElmer radiochemical-calculations URL, and the From / To multipliers (Ci ↔ Bq ↔ dpm ↔ TBq) unit-conversion table. The trailing Rare Disease block lists sPD, GBA-PD, CMT1, AGS, FTLD-Tau prevalences. 1 Uncertain Span (ARG concentration cell mixed Korean / English be approximated verb). The Radiochemical / specific-activity content here is the canonical glossary reference for the framework axes above; specific values should be opened on the source page rather than re-quoted.

20240722_184424 (Pipeline > Radiochemical > Rare Disease > PET) is the rare- disease prevalence table + Lysosomotropic vs LAMP1 binder lysosomal-tracer comparison + Postmortem GBA-PD lysosomal evidence table. The Lysosomotropic block introduces three compounds with promising in-vitro / in-vivo profiles (TR06795533, TR06795793, TR06795792) and notes that TR06795973 has all the desired profile needed for a lysosomal PET tracer with safety and biodistribution remaining (the TR06795973 vs TR06795793 digit confusion is flagged uncertain). Goal: image the abundance of lysosomes in brain and peripheral organs, intended for Gaucher / Hunter / San Filippo. The 20231018 update prioritises Lamp1-binder development because of the larger dynamic window. The Postmortem GBA-PD lysosomal evidence sub-table cites Kurzawa-Akanbi 2012 (n=21, frontal / cingulate, ↑ LAMP1 / LAMP2, ↓ Cathepsin D activity), Gegg 2012 (n=4, putamen, ↑ trend LC3II), Li 2019 (n=6, cingular cortex, mixed ↑ / ↓ LC3II / SQSTM1 / LAMP1 / p-MTOR / p-RPS6 / AMBRA1 / BECN1), and Moors 2019 (n=3-7, frontal cortex / SN, ↓ trend Cathepsin D). The closing REM-Sleep-Behavior-Disorder section starts the PSYCHIATRIC OUTCOMES IN PD heading that continues onto 20240722_184427. 5 Uncertain Spans (rare-disease prevalence column-3 vs column-5 mapping, right-most cropped column, Lysosomotropic compound-ID digit ambiguity, colde study typo, REM-sleep-table left header band).

20240722_184427 (PET > RBD (REM sleep behavior disorder) > Symptom > Incidence) is the four-PPMI-slide PSYCHIATRIC OUTCOMES IN PD / Cumulative Prevalence / PD vs HC over time / PD CHARACTERISTICS CONT. block (GDS-15 / STAI State / MDS-UPDRS Part I subscores Psychosis / Apathy / Fatigue / Insomnia / ESS / RBDSQ / QUIP rates across Baseline / Year 1-5; PD vs HC OR / Year*Group interaction OR; PD / HC / LRRK2 / GBA group means with HC-vs-LRRK2 / HC-vs-GBA adjusted p-values for Blood Pressure OH Drop, STAI, QUIP, Urate, UPSIT raw + categories, ESS, RBDQ; the ICSD-3 RBD diagnostic criteria and the RBD screening questionnaire (RBDSQ) 10-item opening). 4 Uncertain Spans. The page sits in this section because PET is its first nav_path entry, but the visible body is a clinical-scale longitudinal PPMI block; the same evidence is not re-quoted in the biomarkers-outcomes topic, which covers the disjoint RBD / MoCA / Outcome measures first- nav-root sources for that material.

Source Table

All 18 sources, in capture-time order, with the per-page uncertain- span and embedded-image counts copied from front matter. nav path is the full nav_path recorded in the source note.

stemnav path / headingsource notecanonicaluncertain spansembedded images
20240722_183247Microglial Imagingnotemd30
20240722_183250Microglial Imaging > Modelling > NHP > PDEnotemd10
20240722_183252PE > PET > Chemistry PETnotemd50
20240722_183258PETnotemd50
20240722_183301NHP > PDE > PE > PETnotemd10
20240722_1841537T MRInotemd30
20240722_184420Terminology > Psychosis in PD > pipeline > Radiochemicalnotemd10
20240722_184424Pipeline > Radiochemical > Rare Disease > PETnotemd50
20240722_184427PET > RBD (REM sleep behavior disorder) > Symptom > Incidencenotemd40
20240722_184604VMAT Vesicular monoamine transporter-2 > VMAT PET > [18F]AV-133notemd20
20240722_184809[MOLECULAR BIOLOGY] > [PET] > Parameters of PET ligandnotemd60
20240722_184813PK-PD relationship > [PET] > Antibody radiolabelling > Parameters of PET ligandnotemd50
20240722_184816Parameters of PET ligand > Dose of PET tracer > PET Steering Committee > Workflownotemd30
20240722_184819[PHARMACOLOGY] > Parameters of PET ligand > Dose of PET tracer > PET Steering Committee > Workflownotemd40
20240722_184823[MOLECULAR BIOLOGY] > [PET] > Parameters of PET ligandnotemd50
20240722_184826Dose of PET tracer > PET Steering Committee > Workflow > Preclinical studynotemd50
20240722_184829PET Steering Committee > Workflow > Preclinical study > Clinical studynotemd40
20240722_184836[MOLECULAR BIOLOGY] > [PET] > Regulatory Development Path PET ligandnotemd40

Totals across the 18 sources: uncertain_span_count = 66, embedded_image_count = 0. These are review surface area; the zero-figure-embed count reflects the 2026-04-29 body-purity decision (docs/decisions/2026-04-29-body-purity-and-figure-only-embeds.md) under which mixed text-and-figure crops on these pages are kept as evidence rather than embedded.

Uncertainties Carried Forward

This page deliberately does not paraphrase the Patel-Gibson 2008 Bmax / Kd table cell values, the Friden 2014 47-tracer pie-chart percentages, the Honer 2014 Bmax > 1 nM (minimal) / `peak SUV

2 for brain tissue` thresholds, the Hostetler 2016 NHP brain- section figure labels, the McCluskey 2020 outcome-parameter table formulas, the Takeda Bmax-targets PET-tractability rating mapping, the PETSC slide member-roster cells, the Discovery Process to FIH Study row decision-text, the LC-MS cold-tracer triage decision-flow criteria, the [18F]MNI-1054 / Compound 1 / Compound 2 occupancy fit plot Slope / Occ50 cells, the Bavarostat / EKZ-001 / EKZ-317 preclinical-study example cells, the Mosessian 2014 eIND-vs-IND requirement column cells, the NLRP3 PET program tracer iteration / dose / blocking-result cells, the AAV gene-therapy trial table cells, the Cristian Salina sample-size grid cells, the 7T MRI sequence-row physics / clinical-use descriptions, the Mizrahi 2012 TSPO rs6971 polymorphism population-frequency cells, the NBB Case ID color-band assignments, the lysosomotropic / LAMP1-binder compound-ID digit boundaries, the postmortem GBA-PD lysosomal evidence cells, the PPMI psychiatric-outcomes longitudinal table cells, or the ICSD-3 RBD diagnostic-criteria narrative. Specific uncertainty hot spots worth checking before any downstream extraction:

The [3H]MCC950 Ki 11nM vs Kd 92.63nM disagreement on 20240722_184420, the I think there is a typo … should say 450 not 45 operator annotation on 20240722_184604, the confered misspelling on 20240722_183258, and the acieved typo / IND (202508) / pH? (202411) uncertain tokens on 20240722_183252 are preserved verbatim as the source’s own typography rather than reconciled.

  • pet-imaging — section index for the 16 PET / imaging / tracer-development sources
  • microglia-imaging — section index for the 2 Microglial Imaging sources
  • parkin — sibling topic; DATSCAN / 18F-DOPA / FP-CIT SPECT / DTI / neuromelanin MRI on Parkin-PD pages, MJFF MC1 PET in Parkin-PD planning, [3H]BCPP-EF Preclinical-support saturation-binding work on Parkin-PD fibroblast lines
  • mitochondria — sibling topic; MC1 PET / [18F]BCPP-EF tracer mechanism / MIND-MAPS / MPTP-monkey, σ1R [11C]SA-4503 / [11C]UCB-J Imaging-of-MAM block, 31P MRS principle and clinical-trial set, FDG-PET / DNP 13C-MRS adjacent strands
  • inflammation — sibling topic; Imaging neuroinflammation > DPA714 > 3rd Generation TSPO axis, NLRP3 inhibitor program Microglial Imaging > NHP > PDE > PE > PET Bmax / Invicro / 6OHDA-rat / [3H]MCC950 / [3H]TR06616126 / [3H]PBR28 NHP imaging matrix, the Katy / Microglial Imaging cohort-evaluation table
  • biomarkers-outcomes — sibling topic; SV2A imaging (Wilson 2020 #902), Sigma-1 Receptor (σ1R) PET schematic, Retina / Amydis AMDXP-2011P / Bodis-Wollner / Ortuño-Lizarán / Veys 2019 retinal panels, DAT / [18F]AV-133 effect-size and sample-size cells, NfL-vs-imaging atrophy biomarker block
  • parkn-gt — PARKN GT (PFR-4249-100) program entity referencing CSF Parkin protein / Parkin PET / pS65-Ub / MC1 PET / DaTScan biomarker plan
  • nlrp3-inhibitor — NLRP3 Inhibitor (Marianthi) (PFR-4231-100) program entity that consumes the NLRP3 PET tracer chemistry workstream covered here
  • pet — first-nav_path sources rooted at PET
  • pe — first-nav_path sources rooted at PE
  • nhp — first-nav_path sources rooted at NHP
  • 7t-mri — first-nav_path sources rooted at 7T MRI
  • terminology — first-nav_path sources rooted at Terminology
  • pipeline — first-nav_path sources rooted at Pipeline
  • vmat-vesicular-monoamine-transporter-2 — VMAT-2 by-nav index
  • molecular-biology — [MOLECULAR BIOLOGY] by-nav index
  • pk-pd-relationship — PK-PD relationship by-nav index
  • parameters-of-pet-ligand — Parameters of PET ligand by-nav index
  • pharmacology — [PHARMACOLOGY] by-nav index
  • dose-of-pet-tracer — Dose of PET tracer by-nav index
  • pet-steering-committee — PET Steering Committee by-nav index
  • microglial-imaging — Microglial Imaging by-nav index
  • source-catalog — all 447 sources in capture order
  • nav-path-index — 376 distinct nav_paths

그래프 뷰

백링크