Current Status and Future of

Radiopharmaceuticals in Korea

2017. 09. 20

Lee, Kyo Chul

Korea Institute of Radiological And Medical Sciences

Division of RI-Convergence Research

Contents

I. History of PET Radiopharmaceuticals

II. Manufacturing and Hospital Compounding of PET

Radiopharmaceuticals

III. Status of Recently Research for PET

Radiopharmaceuticals

I. History of PET Radiopharmaceuticals

Cyclotron & PET Scanner in KOREA

• 1986’ First cyclotron installed in KIRAMS, 50 MeV • 1994’ First PET scanner & medical cyclotron established in

Samsung Medical Center & Seoul National Univ. Hospital • 1996’ KIRAMS established PET Center

• Now, more than 50 radiochemist & pharmacist work on

radioisotopes & radiophamaceuticals production & research

284 250 256 276 280

249

24 10

12 14 14 11 8

56 85

113 129 148 158 16 23

34

34 34 35

0

50

100

150

200

250

300

350

400

450

500

2006년 2007년 2008년 2009년 2010년 2011년

감마/SPECT SPECT-CT PET PET-CT 사이클로트론

#

‘KSNM‘

Status of Nuclear Medicine Equipment in KOREA

SPECT Cyclotron

-

100,000

200,000

300,000

400,000

500,000

600,000

2005 2006 2007 2008 2009 2010 2011

264,998

295,526

339,075

447,714

513,851 499,425 499,697

57,031

100,530

184,824

248,935

308,663

341,992 366,315

Japan Korea

Comparison of Using [18F]FDG-PET in KOR/JPN

27%

65%

*

‘KSNM‘

13,407 15,794 19,858 25,078 28,307 28,725 29,665 57,301

100,530

184,824

247,933

308,663

341,992 366,315

515,745

555,991 558,242 561,472 583,555

557,615 559,041

0

100,000

200,000

300,000

400,000

500,000

600,000

700,000

2005년 2006년 2007년 2008년 2009년 2010년 2011년

RI 치료 PET 검사 SPECT 검사

검사

및

치료

건수

Current status of Nuclear Medicine Exam in KOR

‘KSNM‘ RI therapy PET diagnosis SPECT diagnosis

209 181 1,192 491 206 133 8,317 6,922 9,135

16,379 14,237 11,942

84,791

154,321

217,835

261,571

313,349

341,145

-

50,000

100,000

150,000

200,000

250,000

300,000

350,000

400,000

2006년 2007년 2008년 2009년 2010년 2011년

심장질환 뇌질환 전신(종양)

검사

건수

Current status of [18F] FDG-PET disease in KOR

(97%)

‘KSNM‘ Cardiac Neuro disease Oncology

II. Manufacturing and Hospital Compounding

of PET Radiopharmaceuticals

Manufacturing vs Compounding Manufacturing Compounding

Producer Manufacturer/industry Hospital Radiopharmacy

Setting Commercial Clinical

Standard GMP Code of Practice

Regulation National medicinal regulatory authority (e.g. FDA)

Professional bodies/institution

Distribution Public distribution Practitioner-patient

Marketing Yes No

Permission Investigational authority New drug application

Ethics committee

Operational Guidance on Hospital Radiopharmacy (IAEA)

Status

Hospital Compounding is a medication that has been approved by the Director of

the Korean Food and Drug Administration for the purpose

of promptly and precisely preparing or dosing the in

patients in need of anticipation of future demand of patient

in form of a certain amount or dosage unit used by a

doctor’s prescription

Use after reporting to public health center

• Based on Pharmacopoeia KP, The Korean Pharmacopoeia (28 items) USP, U.S. Pharmacopoeia National Formulary JP, The Japanese Pharmacopoeia BP, British Pharmacopoeia EP, European Pharmacopoeia Deutsches Arzneibuch Pharmacipee Francaise

• Report the list of in-house compounding PET radiopharmaceuticals to Public Health Center

• Without approval from KFDA • Without GMP

In-house compounding of PET radiopharmaceuticals

1 [13N] Ammonia 8 [11C] Carbon monoxide

2 [15O] Water 9 [18F] FluoroDOPA

3 [11C] Flumazenil 10 [18F] Sodium Fluoride

4 [11C] Methylspiperone 11 [18F] Fluoromisonidazole

5 [11C] Methionine 12 [68Ga] Edotreotide (DOTA-TOC)

6 [11C] Raclopride 13 [82Rb] Rubidium Chloride

7 [11C] Sodium acetate 14 [18F] Fluorocholine

15 [18F] Fluoroethyl-L-tyrosine(FET)

In-house compounding of PET radiopharmaceuticals

d FP-CIT

Dopamine transporter

Brain disorder Parkinson's disease

N

OCH3

O

I

18F

Manufacture PET Radiopharmaceuticals (KFDA Approved 8 items)

e Ammonia f FDOPA

J Nucl Med May 1, 2013 vol. 54 no. 5 723-731

[18F]Florbetaben (Neuraceq)

Stilbene

Benzothiazole

J Nucl Med August 2009 vol. 50 no. 8 1251-1259

[18F]Flutemetamol (Vizamyl)

Benzothiazole

O

N

S

NNH

18FOH

Microdose Clinical Trial. May, 2012 – Jan. 2013 Phase 1 Clinical Trial. Jul. 2013 – Dec. 2013 Researcher Clinical Trial. Jul. 2014 – Aug. 2015 Phase 3 Clinical Trial. Jan. 2015 – Jun. 2016 KFDA Approval

KIRAMS – Futurechem Contracted Alzheimer Dementia Clinical Trials. April, 2012

[18F]FC119S

[18F]FC119S (Alzaview)

III. Status of Recently Research for PET

Radiopharmaceuticals

- Methodology (solvent effect)

- Research trends

HO

H

OH H

OH

H

OH

H

HOH

HO

H

F-O

O

OO

O

O

O

O

F-

H

H

HH

H H

HH

HO

HH

OH

HO

H

HO

HF- Cs+

"naked fluoride" (free)usually from TBAF

"flexible fluoride"

"isolated fluoride"

N+ F-

water solvated fluoride

alcohol solvated fluoride

No more nucleophile and no more base

Too strong nucleophile as well as base

Mild nucleophile and decrease of basicity

SELECTIVITY & REACTIVITY

Protic solvent is known for not good solvent for fluorination, How about bulky alcohol – t-BuOH

Concept

N

OCH3

O

I

18F

N

OCH3

O

I

MsO

RX RF or R[18F]FCsF or 18F-

protic solvent (tertiary alcohols)

protic solvent (tertiary alcohols) OH

CH3H3C

CH3

(t-BuOH)

[18F]fluoride (37 GBq)TBAOH

old method: 1%, 10 mg of precursor, 10 min, 90 oCthis method: 36%, 4 mg of precursor, 20 min, 100 oC

Fluorination in Protic Media

A New Class of SN2 Reactions Catalyzed by Protic Solvents: Facile Fluorination for Isotopic Labeling of Diagnostic Molecules

Kim, D. W.; Chi, D.Y. et. al., J. Am. Chem. Soc. 2006, 128, 16394-16397

Results

OAcOAcO OAc

AcO OTf

ONDMTrO

N

O

OH3C Boc

ONs

entry Compound [18F]fluorination temp. (°C)

Time (min)

Precursor (mg)

Radiochemical yield (%) Product

1 100 10 20 85.4±7.8a (n=10) [18F]FDG

2 120 10 20 65.5±5.4b (n=10) [18F]FLT

Method in literature 110 10 20 15.0±5.4 (n = 3) [18F]FLT

aRadiochemical yield after [18F]fluorination in the manual synthesis (n=10). The product was 2-[18F]fluoro-2-deoxyglucose; b3-Deoxy-3’-[18F]fluorothymidine ([18F]FLT), radiochemical yield after HPLC purification in the automatic synthesis with GE TracerLab FX module (n=10);

The automatic preparations of the key fluorine-18 labeled PET radiopharmaceuticals using alcohol solvent system.

N

OCH3

O

I

MsO

N N OTsOTHP

NO2

entry Compound [18F]Fluorination temp. (°C)

Time (min)

Precursor (mg)

Radiochemical yield (%) Product

3 100 20 4 35.8±5.2c (n=14) [18F]FP-CIT

Method in literature 90 10 10 only 1% [18F]FP-CIT

4 120 15 10 69.6±1.8d (n=10) [18F]FMISO

Method in literature 105 6 10 15.0±5.4 (n = 3)

cN-2-[18F]fluoropropyl-2b-carbomethoxypropyl-3β-(4-iodophenyl)nortropane ([18F]FP-CIT), radiochemical yield after HPLC purification in the automatic synthesis with GE TracerLab FX module (n=14); d1-[18F]Fluoro-3-(2-nitro-imidazol-1-yl)-propan-2-ol ([18F]FMISO), radiochemical yield after HPLC purification in the automatic synthesis with GE TracerLab MX module (n=10).

The automatic preparations of the key fluorine-18 labeled PET radiopharmaceuticals using alcohol solvent system.

HOt-Bu

Cs HOt-Bu

A

C

O

O

OO

H

H

HH

BWeakness of ionic bond strength by H-bonding

H-bonding

H-bonding

Increasing leaving group ability of sulfonates by H-bonding

t-alcohol solvated fluoride "flexible fluoride"

attack

OX

R''SOO

R'

δ-t-BuOH

H-bonding

D Inhibition of side reactions by protic atmosphere

& protic media

Cs F F-

formation

Mechanism of Fluorination

Kim, D. W. et. al. J. Org. Chem. 2008, 73, 957-962.

Mechanism Study : The Formation of Reactive “Flexible fluoride”

OMsF

polar aprotic media

92%t-amylalcohol

CsF

t-amylalcohol

18F-N

OCH3

O

I

18F

N

OCH3

O

I

t-BuOH

N

OCH3

O

I

MsO

polar aprotic media

18F-

HOt-Bu

H-bondingO

XR''SO

O

R'

δ-Inhibition of side reactions by protic atmosphere

& protic media

Mechanism : Selectivity of Fluorination in Non-polar Protic Media

Mechanism of Selectivity

Tau-PET tracer research trend

N

N NH

O18FOH

N

NH

N

18FN

18F

NC CN

[18F]FDDNP

2001 2002 2012 2014 2016 2013 2017

S

NNH11CH3

HO

2015

Inventor Siemens Tohoku Univ.

Developer Eli Lilly GE HeathCare

Clinical Trials Phase II Phase II

Binding Affinity (ki/nM) 14.6 5.19

Selectivity (Tau/Ab) 25 30

logP (calc.) 2.25 2.62

brain kinetics (2/30 min) 3.28 10.3

vs. [18F]MK6240

[18F]JNJ311

25

[11C]PIB

Amyvid

Moving attention to tau-PET research after launch of amyloid-PET

Vizamyl

Neuraceq

[18F]AV1451 [18F]THK5351

New PET tracers High selective radioligands to Tau tangles

26

[18F]MK6240 [18F]JNJ311

Inventor Merck Janssen

Developer Cerveau Tech. Janssen

Progress Phase 1 Preclinical

Binding Affinity (ki/nM) 0.36 7.9

Selectivity (Tau/Ab) >10,000 540

ClogP (calc.) 2.23 3.19

brain kinetics (peak/30 min) (rhesus monkey)

1.8 3.06

NN

N H2N 18F

N

N18F

NH

N

[18F]MK6240 [18F]JNJ311 [18F]MK6240

[18F]JNJ311

Start of Tau-PET R&D 2nd Round

Prostate Cancer

▶Globally, more than one million new cases occur annually: Male cancer incidence second

▶Prostate cancer patients in Korea are steadily increasing

▶Random tissue biopsy is required after screening with serum prostate specific antigen (PSA) levels

▶High recurrence rate after radical initial treatment: 40% biochemical failure

2002 2003 2004 2005 2009 2006 2007 2010 2008 2011 2012 2013 2014 2015 2016

HO2C NH

NH

CO2H

O

CO2H

NH

O

18F

[18F]DCFBzL [18F]DCFPyL

PSMA R2

PSMA 11

PSMA 617

18F-HTK-01070

C-11 F-18

Ga-68

Lu-177, Ac-223 Therapeutics

Diagnostics

Research Diagnostic drug Therapeutic drug

Major PSMA-PET radiopharmaceutical development history

Prostate cancer PET imaging

Small-sized metastatic prostate cancer can not be observed with MRI or CT. [18F]FDG is the most commonly used cancer diagnostic drug, but its prostate cancer intake is low

PET image SPECT image

Prostate cancer target treatment (beta particle isotope)

Three injections every two months Significant recovery (PSA normalization) Recurrence after 1 year

177Lu (β)

Energy: 0.2 to 2.3 MeV Transmittance: 0.5 12 mm in vivo (10-1000 cells) Features: More effective for solid cancer cell mass

treatment

Can treat castor-resistant prostate cancer with resistance to hormone therapy

PET 영상

4 injections every 2 months Significant recovery (PSA normalization) 225Ac (α)

Energy: 5 to 9 MeV Transmittance: 50-90 um in vivo (2 ~ 10 cells) Features: Very small metastatic cancer and cancer cells that

may remain after surgery

Can treat castor-resistant prostate cancer with resistance to hormone therapy

Prostate cancer target treatment (alpha particle isotope)

THANK YOU