pet radiopharmaceuticals and chemistry module for the...

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

1


Trend of molecular imaging

CT(1967)

MRI(1973)

PET(1976)

PET-CT(2001)

1960’s 1970’s 2000’s

2


PET(Positron Emission Tomography)-CT Scanner

3


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

4


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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[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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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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Korea PET scanner & Cyclotron installation map

PETCyclotron

Cyclotron: 38

PET scanner: 140 (PET + PET/CT)

(2010)

Seoul

8


Radiopharmaceuticals

Diagnosis

SPECT PET

PET Radiopharmaceuticals

OncologyNeurologyApoptosisCardiology

Automated production

Labeling

Technology

Precursor

Engineering

Condition

OptimizationPTC

Device

Development

MachineDisposable

Materials

Therapy

Nuclear Medicine

Tech Tree

1

2 3

9


PET Radiopharmaceuticals

Oncology

TumorHypoxia

Neurology

AlzheimerParkinsonDepression

Stroke/Epilepsy

Apoptosis

TumorSclerosis

1

Tech Tree

IP

IP

IP

10


Labeling Technology

Precursor Engineering

Polymer-supportedsalt-supported

Condition Optimization

PTC

Polymer-supported

2

Tech Tree

IP IP

11


Device Development

Machine

One bodyOne button operation

Disposable

Materials

CassetteReagent Kit

3

Tech Tree

IP IP

12


Radiopharmaceutical Production Center

Essential equipments

Cyclotron(~$3,500,000)

Chemistry module(~$150,000)

13


LabelingPrecursor

[18F]FDG heart imaging of rat

[123I]IPT brain imagingof rat

Clinical TrialClinical Trial

Radio-pharmaceutical

General Development of Radiopharmaceuticals

14


Bottle Neck

5

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

15


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

16


A normal human

PET imaging of a brain slice

A patient with moderately severe PD

COOH

18FHO

HO

NH2

[18F]-6-Fluoro-L-DOPA

17


Tracer Distribution in Brain over Time

NO

F

N

NO

18F

[18F]FluoroethylspiperoneDopamine D2 antagonist

18


FDG (Fluorodeoxyglucose) PET image

PET

PET-CT

CT

OHOHO

18F

OH

OH

19


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

20


Tracer Distribution in Heart over Time

[13N]NH3

21


ROI (Region of Interest) Analysis

22


Tissue curve

23


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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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

25


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

26


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

27


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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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

29


GE FASTlab Synthesis Platform ([18F]FDG Mass Production Module)

Automatic Chemistry Module for Routine Production of Radiopharmaceutical

30


GE TRACERlab MX([18F]FDG Mass Production Module)

Disposable cassette


31


GE TRACERlab FX F-N


32


GE TRACERlab FX F-E


33


Chemistry Module: GE TracerLab FX

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[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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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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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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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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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

39


Control

10Gy

20Gy

FLT FDG FLT FDG FLT FDG

Day 0Before Treatment

Day 1 Day 2

Radiation Treatment Response Evaluation with [18F]FLT

40

FutureChem Co., Ltd. Medicinal Chem. Lab., Sogang University41

Human [18F]FLT PET-CT Lung Cancer Image


[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

42


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

43


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

44


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

45


Organization of network

46


FASTlab 1 min snap-on cassetteEasy to set-up, snap-on cassette

47


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

50


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

51


• 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

50


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

51


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

52


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)

53


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.

54


한양대학교의공학과의 무궁한 발전을 기원합니다.

감사합니다.

55


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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