20240722_184836

Regulatory Development Path PET ligand

resource: (Mosessian et al. 2014, PMID 24733693)

		eIND Or FIH	(Traditional) IND
FIH	Purpose	- Microdosing, (P0) (so, SPAL 등은 늘 microdose 이면서, 약은 안 쓰므로 여기에 해당) - target protein 의 distribution - Pk of drug 도 여기부터 시작할 수 있음.
FIH	requirement	- Not Intended for diagnostic or therapeutic - Clinical protocol - Manufacturing under USP 823 or CFR 212 guidelines - Dosimetry studies in rodents - (Non-GLP?) Toxicilogy studies in one species (보통 rat, 부검해야 하므로 day1과 day14 은 별도시험) • CBC, clinical/blood chemistry, necropsy, and histopathology - No safety pharmacology studies • Body weight, rectal temperature, heart rate and rhythm, blood pressure, pulse oximetry, and respiration rate. - No genotoxicity studies	- Clinical protocol - Manufacturing under USP 823 or CFR 212 guidelines - Dosimetry studies in rodents - (GLP) Toxicilogy studies in two species - (GLP) safety pharmacology studies in two species - genotoxicity studies
P2		-
P3		-
NDA		-

Microdosing study

아주 적은 양 ((i. e. not more than either 100 µg or 1/100 of estimated pharmacologically effective dose) 의 약에 radiolabelling 해서 PK 보려는 시험.
주의) 이것은 약에 LABElling 하는 것이므로, SPAL 같은 것에는 해당안 됨.

Outcome of PET radioligand study

BP (Binding potential)
- which is proportional to the specific binding divided by the free concentration of the radioligand [15

Micro PET ligands

◆ D1 Rc
◆ D2 Rc
◆ PDE10A enzyme
Expression and distribution of the target
Binding of 504 to the target
Dose
- D2 antagonist: usually 50% – 90% occupancy: doses associated with greater than 95% occupancy are unnecessarily high, and that those with less than 10% occupancy are unlikely to be efficacious.
Dosing interval
- Retention time in brain
Example
- The measurement of receptor occupancy and pharmacokinetics in brain combined with the evaluation of adverse reactions in a small number of healthy subjects
Is HDAC6 radiotracer available for radioautograph and PET?

	Criteria

regional brain uptake of compounds with the desired affinity (Bmax/KD > 10) along with other desirable physical characteristics (Pgp, log P etc) will be assessed in rodents via LC/MS	the selected compounds show elevated uptake in regions which are known to have high expression of the HDAC6 enzyme
radiolabeling and baseline PET scans performed in NHP.
Clinical translation		ICH M3(R2) regulatory guidance for microdosing (7-day multiple dose iv toxicology study).

Glossary

SUVR	standardized uptake value ratios
DVR	distribution volume ratio
Edge effect	with the edge of tissue, or potential folds in the tissue you can get increased accumulation of activity as it cannot be as easily removed via washing. Hence increase accumulation not caused by specific binding.
	In areas where tissue is shredded/rolling/lifted from the slide due to damage, as one example, tissue does not lay flat and tracer become stuck and be protected from washing.

Database PET

		Search example
MICAD	(https://www.ncbi.nlm.nih.gov/books/NBK5330/
	MICAD available through PubMed: MICAD chapters are now accessible through PubMed. To retrieve a list of all MICAD records, query PubMed for "Molecular Imaging and Contrast Agent Database (MICAD)"[book].
	FDA Approved Contrast Agents: Download a list of FDA approved contrast agents (Latest update: January 2013).
	Molecular Imaging Probes and Contrast Agents List: The MICAD staff has created the Molecular Imaging Probes and Contrast Agents List
	Cortellis Drug Discovery Intelligence (https://www.cortellis.com/drugdiscovery/home?locale=en-US).	"Vesicular Monoamine Transporter 2 (VMAT2) Ligands" AND "Pet" → something in drug/biologics "TAU" AND "Pet"" → something in drug/biologics "Park2" AND "Pet" → nothing, "Parkin" AND "Pet" → nothing "PRKN" AND "Pet" → nothing
GOOGLE

AAV PET

	AAV	Radiotracer	Species	ROA	PK
Seo et al. 2020, (PMID)	PHP.eB	a positron emitter (Cu-64, t_1/2 = 12.7 h)	mice		reported
Seo et al. 2020, (PMID) 2nd		I-124,		intracranial injection to the brain and therefore did not focus on the receptor binding characteristics or endothelial accumulations³¹.
Seo et al. 2020, (PMID) 2nd	reporter gene imaging has been used to measure transduction but cannot quantify PK³².				cannot quantify PK³².

Safety of PET tracer

(NLRP3 pts meeting 20220323) single species, single dose 7-day IV micro dosing toxicity study needed for human studies

Sharefolder of Imaging

Synthesis

Step			Where?
0		Radionuclides are generated from the cyclotron (or generator) in a chemical form that is not predisposed for direct labelling reactions. For example, F-18 is normally obtained as an aqueous [18F]fluoride solution from the target that is chemically inactive
1	activation of radionuclide	This is achieved by azeotropic drying with acetonitrile in presence of an aminopolyether as phase transfer catalyst. (2010 Wadsak)
2	radiolabelling	The activated radionuclide is subsequently coupled with or incorporated into the predesigned predecessor of the vehicle molecule (=precursor). This labelling reaction often requires elevated temperature or microwave assistance and is performed in dedicated synthesizers.	우리가 precursor 를 Dana Farber 로 보내나?
3	Purification of the product	the crude product is purified via solid phase extraction cartridges (SPE), formulated for intravenous injection and sterile filtrated under aseptic conditions.
	Shipping to Takeda	Dana Farber 에서 Synthesis 후 (18F-FE-PE2I) 의 형태로 Takeda 로 shipping.

Timeline

(Slide block — flowchart, evidence-only, transcribed labels)

Timeline and Process to Conduct Human TO PET Study

Top swimlane (purple boxes): Site selection — Suitability assessment — Scale up production of precursor and reference standard (4 mo) — Compile CMC Data Package (2 mo / 1.5 mo) — GMP radiochemistry development and validation runs — Final site qualification and CMC approval

Middle swimlane: Pre-clinical contracting (green) — Clinical contracting for TO PET study (green, 4 mo / 6 mo)

Bottom swimlane: Pre-clinical validation of PET tracer as fit-for-purpose (yellow) — In vivo PET imaging — Clinical contracting for tracer validation (green)

Legend swatches:

■ Site selection, material & radiochemistry prep
■ Contracting
■ In vivo PET imaging
■ Tracer toxicology
■ Protocol development and regulatory approval

Uncertain Spans

location	transcription	uncertainty
Regulatory Development Path PET ligand table, “Manufacturing under USP 823 or CFR 212 guidelines”	`USP 823`	The numeric `823` is small print; in the original FDA/USP nomenclature this is typically `USP <823>` (PET monograph), but the angle-bracket markers are not visible in the photo.
AAV PET table Seo et al. rows	`(PMID)`, `(PMID) 2nd`, `(PMID) 2nd`	Three rows reuse the same `Seo et al. 2020, (PMID)` shorthand; the literal `(PMID)` placeholder appears in the source without an actual PMID number.
Sharefolder URL	long mytakeda.sharepoint URL with %2D encoded GUID	The URL contains URL-encoded segments and is broken across multiple lines in the source; reassembled best-effort but trailing fragment after `%2Dd1b93a9fc` may be truncated.
Synthesis row 0 / Activation row	`(2010 Wadsak)`	The citation is in small print; the trailing Korean comments visible in the upper region may belong to row 0 or row 1 — assigned to row 1 based on visual alignment but not crisp.

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