pet radiopharmaceuticals and chemistry module for the...
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
PET Radiopharmaceuticals and Chemistry Module for the Automated Production
PET Radiopharmaceuticals and Chemistry Module for the Automated Production
2011. 4. 4
Dae Yoon ChiSogang UniversityFutureChem Co., Ltd.
한양대학교 공과대학 의공학과
[email protected]://medchem.sogang.ac.krhttp://www.futurechem.co.kr
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Trend of molecular imaging
CT(1967)
MRI(1973)
PET(1976)
PET-CT(2001)
1960’s 1970’s 2000’s
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
PET(Positron Emission Tomography)-CT Scanner
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Labeling
§ Sensitivity, Easiness, Structure-Activity Relationship, Specificity, Penetration.
§ Radioisotope Labeling 10-18 mol
§ Fluorescence Labeling 10-12 mol
u in vitro
u microscope
§ UV (Ultraviolet) 10-6 mol
§ Spin Labeling
§ Photoaffinity Labeling
u in vitro
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Isotopes for SPECT for PET
Name t1/2
Tc-99m 6 hI-123 13 hTl-201 3.04 dayXe-133 5.24 dayI-131 8 dayGa-67 3.26 dayIn-111 2.81 dayCr-51 27.7 day
Name t1/2
C-11 20 minN-13 10 minO-15 2 minF-18 109 minCu-64 12.7 hGa-68 68 minRb-82 1.3 minI-124 4.18 d
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
[18F]FDG-PET Scans: Trend at Korea
0
20000
40000
60000
80000
100000
120000
140000
160000
180000
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
PET Scans: Trend at Korea (핵의학회 제공)
0
50000
100000
150000
200000
250000
300000
1994 1997 2000 2001 2002 2003 2004 2005 2006 2007 2008
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Korea PET scanner & Cyclotron installation map
PETCyclotron
Cyclotron: 38
PET scanner: 140 (PET + PET/CT)
(2010)
Seoul
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Radiopharmaceuticals
Diagnosis
SPECT PET
PET Radiopharmaceuticals
OncologyNeurologyApoptosisCardiology
Automated production
Labeling
Technology
Precursor
Engineering
Condition
OptimizationPTC
Device
Development
MachineDisposable
Materials
Therapy
Nuclear Medicine
Tech Tree
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2 3
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
PET Radiopharmaceuticals
Oncology
TumorHypoxia
Neurology
AlzheimerParkinsonDepression
Stroke/Epilepsy
Apoptosis
TumorSclerosis
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Tech Tree
IP
IP
IP
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Labeling Technology
Precursor Engineering
Polymer-supportedsalt-supported
Condition Optimization
PTC
Polymer-supported
2
Tech Tree
IP IP
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Device Development
Machine
One bodyOne button operation
Disposable
Materials
CassetteReagent Kit
3
Tech Tree
IP IP
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Radiopharmaceutical Production Center
Essential equipments
Cyclotron(~$3,500,000)
Chemistry module(~$150,000)
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
LabelingPrecursor
[18F]FDG heart imaging of rat
[123I]IPT brain imagingof rat
Clinical TrialClinical Trial
Radio-pharmaceutical
General Development of Radiopharmaceuticals
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Bottle Neck
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Several hundred candidates have been developed for 40 years:
FDG has only been used widely.
HN
NHNH
HN
NO
H
OO
O
OHN NHPbf
NH
NH2
tBu-O
O
Several hundred candidates of Radiopharmaceuticals
Technology?
Bottle Neck
FDG is only used
Problem
Mass productionNeedPrice
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Cancer detection Brain imaging
Finding New RA1
Precursor18F
18F-
Precursor
Labeling technology2
Autosynthesis3
Clinical Application
From Benchto Patient
Non-Stop Service
Short half-life
4
PET
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
A normal human
PET imaging of a brain slice
A patient with moderately severe PD
COOH
18FHO
HO
NH2
[18F]-6-Fluoro-L-DOPA
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Tracer Distribution in Brain over Time
NO
F
N
NO
18F
[18F]FluoroethylspiperoneDopamine D2 antagonist
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
FDG (Fluorodeoxyglucose) PET image
PET
PET-CT
CT
OHOHO
18F
OH
OH
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
42세 유방암 여성 환자의 전신 PET영상
Lt SCL LNRt SCL LN
Lt Paratracheal LNcoronal
Rt SCL LNLt SCL LN
transaxial
Lt SCL LN
sagittal
OHOHO
18F
HO
OH
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Tracer Distribution in Heart over Time
[13N]NH3
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
ROI (Region of Interest) Analysis
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Tissue curve
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Bottle neck: Finding New RA
1. Specific binding or not
2. Specific binding: Protein – disease correlation
3. Animal model
4. PoM (proof of mechanism)
5. What are the most hot compounds to develop?
1. Florbetaben – BSP – Phase 32. Florbetapir – Avid-Siemens – Phase 33. F-PIB – GE – Phase 3
1
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
1. Aliphatic fluorination – almost solve
2. Aromatic fluorination – still need for electron rich system1. Most Urgent: F-DOPA with high specific activity2. Flumazenil: SNU bundang hospital-FutureChem 15-20% yield
in automation
Bottle neck: Labeling technology – F-182
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Bottle neck: Clinical Trials4
1. Cost of clinical trials
2. Korea: If human trial exists: Phase 3 – 3-5 MU$No human trial exists: Starting from Phase 1 –no experienceAmerican FDA approved: very easy to get an approval from Korea FDA – Reverse case?
American: Starting from Phase 1 – No data
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Bottle neck: Business of New RA
1. Minimum production per each batch.
2. Seoul – High population density
3. FLT – two scans required to see the progress of cell proliferation by chemotherapy or radiation therapy
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
CyclotronProduction
SystemRadiophar-maceuticals
Own Hospital
Other Hospitals
§Chemistry ModuleGE-MXFDG
§Devloping Chemistry SystemGE-MXPurification ModuleFormulation ModuleFLTFP-CITAlzheimer (BSP, FC)FESFMISO…..
§Developing FutureChem SystemiModulePurification ModuleFormulation Module
18F-
§Cassette§Reagent Kit
PrecursorSeveral chemicals
§Software (security system)
3Bottle neck: Automatic Synthesis
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
A [18F]B + A + C + D + E + ….18F-
10~30 mgproduct precursor
byproducts
purification à HPLC (semi-prep. < 2 mg)
should be removed
Removable precursors → filtration → HPLC
Purification Problem
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
GE FASTlab Synthesis Platform ([18F]FDG Mass Production Module)
Automatic Chemistry Module for Routine Production of Radiopharmaceutical
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
GE TRACERlab MX([18F]FDG Mass Production Module)
Disposable cassette
Automatic Chemistry Module for Routine Production of Radiopharmaceutical
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
GE TRACERlab FX F-N
Automatic Chemistry Module for Routine Production of Radiopharmaceutical
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
GE TRACERlab FX F-E
Automatic Chemistry Module for Routine Production of Radiopharmaceutical
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Chemistry Module: GE TracerLab FX
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
[18F]FLT Production Data
Phase III Clinical trials: 2004/10/13 ~ 2006/06/05
Patient no.: 110
Production no. of [18F]FLT:
Average radiochemical yields:
37.6 ± 14.3% & 58.2 ± 10.6% (before & after alcohol methods)
(decay-corrected yield after HPLC purification)
0
10
20
30
40
50
60
70
80
90
100
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
18F
Chemistry
Module
Purification
Module
Formulation
Module
• Small space• Low prices• Short synthetic time• Lower radiation
One body System
One body System
18F
•Big space•High prices•Long synthetic time•Higher radiation
Difficult Connection
Automation for FDG
For Other RA: need
modification
Purification module (HPLC
system)
Formulation Module
Conventional System
Conventional System
One body System
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Background
u Unveil of new PET radiotracers
ü [18F]FLT, [18F]FP-CIT, [18F]Florbetaben, [18F]Florbetapir, [18F]Flutemetamol etc.
u Differentiated automatic modules are required
ü [18F]FDG: Only chemistry modules are required at production stage
ü New PET tracers: Chemistry module, Purification module, formulation Module
u Rising demand for customized modules for brand-new PET tracers
ü [18F]FLT, [18F]FP-CIT, FC119S and beyond
ü Embedded with our patented technologies
u Build-up of a network for development of a new module
ü FutureChem, CSCAM, Asan Medical Center
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Ø No true “All-in-one”-type automated chemistry modules in the market
Ø No cassette-type chemistry modules (not applicable to multiple tracers)From researchers’ view points:
Ø No way to utilize our patents and ideas with commercially available chemistry modules (solid phase precursors, microwave reactors etc.)
Ø No integrated user interface (labeling process, UV & RI monitoring system) on the same control panel
Ø Limited access to operating software to customize the sequences of program
Why should we develop ?
Key words : All-in-one, Kit, Multiple tracers
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
O
N
N
O
O
CH3
DMTrO ONos
BOC
18F-/CH3CN
1 N HClO
N
HN
O
HO
18F
CH3
O
O
N
N
O
O
CH3
DMTrO
BOC
18F
[18F]FLT – Synthesis
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Control
10Gy
20Gy
FLT FDG FLT FDG FLT FDG
Day 0Before Treatment
Day 1 Day 2
Radiation Treatment Response Evaluation with [18F]FLT
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University41
Human [18F]FLT PET-CT Lung Cancer Image
FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
[18F]FP-CIT PET imaging tool for Parkinson patient
SPECT imaging ([123I]FP-CIT)-NormalPET imaging ([18F]FP-CIT)-Normal
Commercially Availablein KOREA
More advanced imaging!!
Commercially Availablein Europe
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
기준 및 시험방법설정 및 신청
안전성 자료 획득
유효성 자료 획득
임상시험(IND)
품목허가(NDA)
[18F]FLT방사성의약품 제품화 추진 상황
2004. 7 한국 IND – Phase III – 세계 최초2004. 12 미국 IND (NCI-GE)2006. 12 한국 NDA 신청2008. 4.22 한국 NDA 허가 - 사용가능
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Korea FDA approvals of [18F]FLT and [18F]FP-CIT
Using this technologyUsing this technology
[18F]FLT: April 22, 2008[18F]FLT: April 22, 2008
[18F]FP-CIT: May 19, 2008[18F]FP-CIT: May 19, 2008
Parkinson Patient
Normal
F-18 Labeling Original Technology
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
PET (F-18) Radiopharmaceuticals for AD
Product Company Stage
[18F]AV-1[18F]Florbetaben
BSP Phase III
[18F]AV-45[18F]Florbetapir Eli Lilly (Avid) Application
for NDA[18F]F-PIB[18F]Flutemetamol GE Phase III
6-[18F]F-BTA Bundang Seoul National University Hospital Phase 0
[18F]FC119S FutureChem Phase 0
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Organization of network
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
FASTlab 1 min snap-on cassetteEasy to set-up, snap-on cassette
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
FASTlab FDG Cassette• All-in-one, preloaded with
pharmaceutical grade reagents• Single use…all parts and components
in contact with reagents are contained within the cassette
• Manufactured under cGMP standards in controlled environment
• Single set of Certificate of Analysis for cassette components and reagents
• Entire liquid path is contained within a single use cassette
• Disposable cassettes avoid risk of cross-contamination when different tracers are produced with the same module
Making cGMP compliance easier to achieve
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
FLT(1) produced with FASTlab…
• Yield (*) : 25% yield (uncorrected)
• Synthesis time (*) : 35 min(synthesis)
§ + 7 min (purification)
• Radiochemical purity (*) >95%
O
NosO
NTrO
NBoc
O
O
Protective groupProtective group
Leaving groupReactive site
K222/K2CO3/18F-
O
18F
NTrO
NBoc
O
O
Labelling stepFLT
DeprotectionStep 18F
O
HO
N
NH
O
O
FLT
(*) Before optimization
(1) FLT = 18 F-labeled-thymidine, used in imaging cell proliferation
WIP
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
• 2 steps for synthesis
• Only Chemistry module[18F]FDG
• 1 steps for synthesis
• Purification, formulation modules[18F]FP-CIT• 2 steps for synthesis
• Purification, formulation modules[18F]FLT
Automatic chemistry Module
Purification
Module
Formulation
Module
[18F]FDG Chemistry module
Basic concept
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
2nd Generation Prototype Module:Hot Reaction results
[18F]FDG production yields:
Most critical figures in the evaluation of a chemistry module’s overall performances
Our achievements
1. [18F]FDG production yield : ca 50% (n=20) non-decay correction yield
2. No failure cases reported yet in a series of reactions
c.f., Mx module in AMC
[18F]FDG production yield : ca 40-50% decay correction
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
GE Mx mCUBE series
Application [18F]FDG only [18F]FDG, [18F]FLT, [18F]FP-CIT, FC119S and …
Synthetic function Synthesis only Synthesis, purification, formulation possible
HPLC compatibility None Integrated
PC-PLC comm. RS232c serialcommunication Ethernet based communication
Monitoring system RI graph RI and UV are monitored graphically
Reactor heating Electric heater Electric heaterMicrowave heating and camera are scheduled.
Comparisions of mCUBE with GE Mx
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Ongoing schedule
vHardware- Microwave heating reactor system
- Reaction monitoring camera
- New disposable cassettes (newly designed shapes and materials)
- Size reduction (70X65X50 -> 60X65X45)
vSoftware- Provision of a uniform solution regardless of the tracer
(FC-119S, [18F]FP-CIT, [18F]FLT and others)
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
Acknowledgments
§ 첨단의료기기 사업본부
§ PET 방사성의약품 융합연구단
§ 서강대학교 화학과 의약화학연구실
§ 주)퓨쳐켐, 주)CSCAM
§ 서강대학교 기계과 이철수 교수연구실
§ 아산병원 핵의학과 오승준 교수연구실
§ Financial supports of Korean Ministry of Education, Science and Technology.
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
한양대학교의공학과의 무궁한 발전을 기원합니다.
감사합니다.
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FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University
1. PET 방사성의약품 융합연구단 2세부과제2. 이철수 교수, 오승준 교수, 허은영 박사, 김종민 박사3. 현재 prototype 시제품 P2 – 아산병원에 있음
1. Cassette type2. FDG 50% (non decay corrected) - CM3. FC119S (Alzheimer Disease) – CM-PM-FM
4. 다음 prototype 시제품 P3 – 거의 완료1. 지원자 모집 – 계약서 작성2. P2에서 최적화된 프로그램 지급3. P3에서도 잘 되는지를 확인 – CM4. P4, P5, P6 등 계속 해서 만들 계획임
5. 무엇을 개발하느냐1. FC119S 2. Florbetapir3. Florbetaben4. F-PIB5. 생산시스템을 다 개발해놓으면 기술이전이나 상업화가 가능함.
자동합성장치 개발 계획
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