20240722_184816

			administration
TRV	Test-retest value	|OP − OP| / ((OP − OP)1/2) × 100%	Average variation of OP from two scans on the same subject without intervention
COV	Coefficient of variance	SD/μ × 100%	Average variation of OP within a group
ICC	Intraclass correlation coefficient	BSMSS − WSMSS / [BSMSS + (k − 1) × WSMSS]	Comparison of reliability of within-subject variability to between-subject variability

Assay flow and criteria in lead optimization

Compound synthesis

• □ possible structure for radiolabeled compound

In vitro assays

• □ potency and selectivity ✓ IC₅₀<20 nM & >50x selectivity
• □ lipophilicity ✓ Log D<2.5
• □ MDR1 ratio ✓ <2.5

Brain PK

• □ fub ✓ >5%
• □ brain penetration ✓ Kp>0.5
• □ brain amide in mice ✓ <50% relative to unchanged

Further profiling

• □ monkey PK (CSF) ✓ BBB permeable & low CSF amide relative to unchanged
• □ target occupancy ✓ specific binding (SB) with KO mice and CN pretreatment
• □ metabolite ID ✓ little human-specific/brain-penetrable metabolite

Radiochemistry development

Preclinical PET study

Dose of PET tracer

Resultant maximal receptor occupancy needs to < 1-5% to avoid pharmacological effect!

	Specific activity (fixed) Specific activity can be convertd to molarity if we know MW (https://www.perkinelmer.com/lab-products-and-services/application-support-knowledgebase/radiometric/radiochemical-calculations.html#Radiochemicalcalculations-Molarityofacarrer-freeradionuclide)		If dose	Then Activity	Receptor occupancy
11C raclopride (Yao 2012)		Mice		0.3 MBq	1%
		rat		5.2 MBq	1%
11C raclopride (Kung 2005)	1,000 Ci/mmol (1 uCi=1 pmol)	human	10 mCi		<1%
a high-affinity brain ligand (Kd 0.1 nM), (Lancelot 2010)		mice	~5 nmol/kg	0.1 MBq (=2.7 uCi)	1%
HDAC6		Cyno)	3.8 mCi/4.9kg
11C CFT (Kung 2005)		Human	459 mCi/70kg		<1%
		mouse	130 uCi/25g		<1%
		rat	2 mCi/300g		<1%
Paul McQuade		mouse	100 uCi (=25 ng/25g?)
		human	PET tracers administered at low mass (1-5 µg)

PET Steering Committee

• Held every month (3^rd week Thursday)

PET Ligand Development Steering Committee (PETSC)

Format:

• Centralized strategy meeting to discuss and plan PET tracer discovery and development efforts to propose to TDT/CST
• Expand to include all internal PET tracer efforts across all Therapeutic Areas
• Establish formal charter, with required representation from all relevant disciplines:
  • QTS Imaging (coordinator), Med Chem, Biology, and DMPK; Monthly meeting minutes maintained

Responsibilities:

• Decision body for feasibility, technical matter, and execution for all PET discovery/development efforts excluding PPP activity
• Evaluation and ratification of proposals to start new PET tracer discovery campaign
  • For TO, program team must present strategic overview of current status, timelines and added value of PET tracer
  • Representation of resource owners, or clear mechanism to obtain resources if strategy agreed at meeting
  • Includes fully-internal programs as well as outsourced or out-partnered
  • Alignment with DDU, Project Team and TDT/CST (GPT)
• Updates on ongoing PET tracer campaigns
  • Clear decisions and actions documented and followed up
  • Templated presentations with clear expectations, and quality discussion on all aspects of PET tracer development (e.g. Med Chem efforts, assay development, in vitro and in vivo imaging efforts)
• Terminations of PET tracer campaigns (e.g. portfolio program terminated, or target deemed intractable)

Function	Regional Sites
	Shōnan	TCAL	TBOS
DMPK	Maki Miyamoto	Anne Kanta	As needed
Med Chem	Izumi Nomura	TBD	As needed
Biology	As needed	Daniela Radl	As needed
QTS	Akihiro Takano	Erica Bradshaw	Paul McQuade*
NS TREM	As needed	As needed	Takeshi Seita
Project Management	Hiroyuki Inuzuka	As needed	As needed

* Meeting Chair

Takeda Pharmaceutical Company Limited

• Sharefolder https://mytakeda.sharepoint.com/sites/PET2/Shared%20Documents/Forms/AllItems.aspx

Discovery Process to Achieve PET Tracer FIH Study

Process Stage	Project Team Operational Lead	Financial Responsibility	Governance
Quantify target expression (Bmax) across species along with regional distribution to inform PET tracer viability	QTS Imaging	DDU*	PETSC#
Using SAR and desired physical characteristics select parameters that will allow for rational PET tracer design	Med Chem	DDU*	DDU*
Non-imaging methods to triage selected compounds and assess specific target binding	DMPK	DDU*	DDU*
In vivo preclinical PET imaging to assess regional distribution and blocking by drug candidate	QTS Imaging	DDU*	DDU*
Clinical Translation	QTS Imaging	GPT	QTSPRF°

* DDU responsible pending QTS post-integration budget
# PET Steering Committee – will decide feasibility and oversee execution of PET Ligand development by PET Development Teams
° QTS Protocol Review Forum

Takeda Pharmaceutical Company Limited

Workflow

Discovery Process to Achieve PET Tracer FIH Study

Process Stage	Lead
Identification of structural class of compounds which shows high selectivity for identified target	Project Team
Quantify target expression (Bmax) across species along with regional distribution to inform PET tracer viability	Imaging
Using SAR and desired physical characteristics select parameters that will allow for rational PET tracer design	Project Team with Imaging input
Non-imaging methods to triage selected compounds and assess specific target binding	Imaging
In vivo preclinical PET imaging to assess regional distribution and blocking by drug candidate	Project Team with Imaging input
Clinical Translation	Imaging

to Fushimi: nomrally we start feasibility discussion during LG before PE (js so we can include PET proposal in PE proposal)

Feasibility assessment begins

Compound synthesis

• □ Possible structure for radiolabeled compound

Uncertain Spans

• “Cyno)” — ‘Dose of PET tracer’ 표 species 셀이 ‘Cyno)‘로 닫는 괄호만 보임. 원문이 ‘Cyno’ 라는 약어 뒤에 닫는 괄호만 남은 형태로 보여 그대로 전사.
• ‘Discovery Process to Achieve PET Tracer FIH Study’ 슬라이드 두 번째 버전 ‘In vivo preclinical PET imaging…’ row의 Lead 셀 — 색상 row 폭이 좁아 ‘Project Team with Imaging input’이 정확한지, 동일한 라벨이 반복된 것인지 photo 해상도 한계로 완전히 확정 불가.
• ‘|OP − OP| / ((OP − OP)1/2) × 100%’ TRV 셀 — 첨자 OP1, OP2 가 ‘OP - OP’ 형태로 보이며 첨자 숫자가 잘 보이지 않음. 시각적으로 구분 어려워 본문은 평문으로 전사.