Van Gen tot Geneesmiddel: Nuclear Imaging techniques …wimu/EDUC/PET-PART2.pdf · Nuclear Imaging...

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Nuclear Medicine & PET ResearchNuclear Medicine & PET Research

Van Gen tot Geneesmiddel:Van Gen tot Geneesmiddel:Nuclear Imaging techniquesNuclear Imaging techniques

Part 2.Part 2.radiopharmaceutical chemistryradiopharmaceutical chemistry

BertBert Windhorst ([email protected])Windhorst ([email protected])Radiopharmaceutical scientistRadiopharmaceutical scientistVU University Medical Center AmsterdamVU University Medical Center Amsterdam

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OutlineOutline

Radiochemistry generalRadiochemistry general

1111CC chemistrychemistry

1818F chemistryF chemistry

8989Zr chemistryZr chemistry

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Half Half lifelife

Short half lives Short half lives demanddemand fastfast productionproduction processesprocesses

1111C : C : 20 min half life: max20 min half life: max 60 60 minutesminutes1818F : F : 110 min half life: max110 min half life: max 240 240 minutesminutes

YieldYield ::At At leastleast 750 750 MBqMBq

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Reaction speed and yieldReaction speed and yield

55 1010 151500

2525

5050

7575

100100

(%)

(%)

55 1010 151500

2525

5050

7575

100100

(%)

(%)

time (min)time (min)time (min)time (min)

5


SpecificSpecific activityactivity

AmountAmount of of radioactivityradioactivity / / massmass

StartingStarting materialmaterial of of allall 1111C chemistry : C chemistry : 1111COCO22

In In thisthis case : case : 1111C / C / 1212CC

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SpecificSpecific activityactivity

Receptor studies : at Receptor studies : at leastleast 18.5 18.5 GBqGBq//µµmolmol((injinj 370 370 MBqMBq = 20 = 20 nmolnmol = 6 = 6 -- 10 10 µµg)g)

1111C : C : EveryEvery 20 20 minutesminutes the SA is the SA is halvedhalved!!

EveryEvery productionproduction alsoalso maxmax 20 20 nmolnmol 1212COCO22

Air Air containscontains 0,03% 0,03% 1212COCO22 : 20 : 20 nmolnmol = 1.5 ml of air!= 1.5 ml of air!

In practice : Yield In practice : Yield = 2= 2--5 5 GBqGBqSASA = 50= 50--100 100 GBqGBq//µµmolmol

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1111C chemistryC chemistry

Ideal isotope: every organic molecule has CarbonIdeal isotope: every organic molecule has Carbon

Large variety of chemical reactions possibleLarge variety of chemical reactions possible

Half life good for PET studyHalf life good for PET study

Radiation burden to patient/volunteer smallRadiation burden to patient/volunteer small

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Possibilities : Possibilities : 1111CC1111COCO22

1111COCO1111CHCH44

HH1111CNCN1111CHCH22OO

1111CHCH33OHOH

1111CHCH33II1111CHCH33II

Zn Zn 400 400 °°CC

Pt, HPt, H22360 360 °°CC

II2 2 (g) (g) 720 720 °°CC

LiAlHLiAlH44--40 40 °°CC

LiAlHLiAlH44 , 20 , 20 °°CC

HIHI130 130 °°CC

Pt, NHPt, NH33360 360 °°CC

1111CHClCHCl33

1111CHCH22NN22

HH22NNHNNH22KOH, 60KOH, 60 °°CC

ClCl22, CuCl, CuCl22310 310 °°CC

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1111C chemistry examples: C chemistry examples: TaxotereTaxotere

C11OH

O

O O

Cl

Cl

Cl

Cl

C11

OO OOH

OHOH O

O

OH

NHO

OO

O

OC11

CH3Li1) 11CO2, Et2O 15°C, 3'

2) HCl in Et2O

1,2,2,2-tetrachloroethyl chloroformate

THF, pyridine, 50 °C, 3 min

pyridine, 65 °C, 7 min

Tax-NH2

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1111CHCH33II

N

N

N O

O

O

F

11CH3

O

NH

N

ClO

OHCl

11CH3

NN

O

Cl

11CH3

NO

O N

O

O

11CH3

N C11 H3

Cl

OH

FlumazenilFlumazenilPK11195PK11195

VerapamilVerapamil

RacloprideRaclopride

SCH23390SCH23390

S

N

NH2

CN

C11 H3DASBDASB

N

HC11 H3

OH S

NNH

C11 H3

DeprenylDeprenyl PIBPIB

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[[1111C]Fumazenil : GABAC]Fumazenil : GABAAA

0.0

2.0

4.0

6.0

8.0

10.0

12.0

[und

efin

ed]

0.0

2.0

4.0

6.0

8.0

10.0

12.0

[und

efin

ed]

12


[[1111C]DASB : serotonine transporterC]DASB : serotonine transporter

Citalopram treatment: Citalopram treatment: 2020 mg/day for 4 weeksmg/day for 4 weeks 0%

20%

40%

60%

80%

100%

0 20 40 60 80O

ccup

ancy

10 mg 20 mg

Plasma Plasma paroxetine (paroxetine (µµg/Lg/L))

Courtesy of CAMHCourtesy of CAMH

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1818F F radiochemistryradiochemistry

Fluoride or FluorineFluoride or Fluorine

Fluoride: Fluoride: 1818FF--

Fluorine: [Fluorine: [1818F]FF]F22

Different chemistryDifferent chemistry

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1818F nucleophilic F nucleophilic substitutionsubstitution

AliphaticAliphatic : at primary or secondary C atoms: at primary or secondary C atoms

Typical STypical SNN2 mechanism2 mechanism

R L

H

HF18 R

H

H18F-

Leaving group: Halogens, Leaving group: Halogens, sulphonatesulphonate estersesters

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1818F nucleophilic F nucleophilic substitutionsubstitution

AromaticAromatic ::

Leaving group: Nitro, Leaving group: Nitro, trimethylammoniumtrimethylammoniumEwEw : nitro, amide, : nitro, amide, nitrilnitril, , aldehydealdehyde

LEw

LEw

F18F18

Ew18F- -

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1818F ChemistryF Chemistry

RL

RF18

18F- +

PTCK[2.2.2]/K2CO3 or(n-Bu)4NH4CO3

SolventHeat 5 - 30 min

OH

F18

OHOH

OOH

OAc

F18

OAcAcO

OAcO

OAc

OSO2CF3

OAcAcO

OAcO

[[1818F]FDGF]FDG

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1818F F WorkWork upup

No fluorination in presence of waterNo fluorination in presence of water

AzeotropicAzeotropic distillation with distillation with AcetonitrilAcetonitril

““nakednaked”” fluoride impossible in organic solvent : fluoride impossible in organic solvent : Phase Phase tranfertranfer catalyst, PTCcatalyst, PTC

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TypicalTypical reactionreaction conditionsconditions

PTC : crownPTC : crown--ether or ether or AmmoniumsaltAmmoniumsalt

CrownetherCrownether: Counter ion needed, K: Counter ion needed, K++

Krytofix[2.2.2] optimal :Krytofix[2.2.2] optimal :

OO

N

OO

NO

O

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TypicalTypical reactionreaction conditionsconditions

Solvents : Solvents : aproticaprotic and and dry to get dry to get 1818FF-- reacting as reacting as nucleophile, not as basenucleophile, not as base

Acetonitrile,Acetonitrile, THF, DMSO, THF, DMSO, dioxanedioxane, (, (chloro)benzenechloro)benzene(DMF)(DMF)

Temperatures : 80Temperatures : 80--180 180 °°CC

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1818F chemistry examples: F chemistry examples: FLTFLT

MartinMartin(2001)(2001)

OO

N N

O

O

dMTr

NOS

boc

OO

N N

O

O

dMTr

F18boc

OOH

N NH

O

O

F18

18F

H+

[18F]FLT

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[[1818F]FLT: imaging cel proliferationF]FLT: imaging cel proliferation

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1818F chemistry example: F chemistry example: FPFP--ββ--CITCIT

N OO

I

F18

NH

OO

I

SO

O

O

Br F18 Br

+

+ 18F-

KI, DiPEA

DMF, CH3CN150°C, 30'

K[2.2.2], K2CO3

CH3CN, 110 °C, 5'

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[[1818F]FPF]FP--ββ--CITCIT

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1818F F FluorineFluorine reactionsreactions

SiR3F18

[18F]F2 / Ne +

RxRx

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1818F F FluorineFluorine reactionreaction

FF--DOPADOPA

NHO

O

O

Si

OO

boc

boc

NHO

O

OO

Oboc

boc

F18

NH2

OH

O

OHOH

F18

[18F]F2 +

H+

freon

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8989ZrZr chemistrychemistry

Coordination chemistry: radiometalsCoordination chemistry: radiometals

Lone pair electronsLone pair electrons

Hydration or coordination ligandHydration or coordination ligand

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8989ZrZr4+4+

6 coordination, 6 coordination,

DesferalDesferal

NH2

NHO

N O

NH

N

O

N

O

OH

OH

OH

O

desferal(Df)

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NH2

NHO

N O

NH

N

O

N

O

OH

OH

OH

ONH

NHO

N O

NH

N

O

N

O

OH

OH

OH

OOH

O

O

NH

NHO

N O

NH

N

O

N

O

OH

O

O

OO

O

O

Fe3+

F F

FF

NH

NHO

N O

NH

N

O

N

O

OH

O

O

ONHO

O

Fe3+

OH

ONH

NHO

N O

NH

N

O

N

O

OH

O

O

O O

Fe3+

desferal(Df)

N-succinyldesferal(N-sucDf) N-sucDf-Fe

TFP-N-sucDf-Fe mAb-N-sucDf-Fe

12

3 4


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NH

NHO

N O

NH

N

O

N

O

OH

OH

OH

ONHO

ONH

NHO

N O

NH

N

O

N

O

O

O

O

ONHO

O

Zr89 4+

mAb-N-sucDf mAb-N-sucDf-89Zr

6

5

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GMPGMP

Good Manufacturing PracticeGood Manufacturing Practice

ValidationValidation

Standard Operating Procedures (Standard Operating Procedures (SOPSOP’’ss))

Clean room technologyClean room technology

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GMP GMP cleanroomcleanroom

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GMP GMP cleanroomcleanroom

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SOPSOP’’ss

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Specifications [Specifications [1111C]FlumazenilC]FlumazenilAlgemeenAlgemeen EisenEisen Vrijgifte SpecificatieVrijgifte Specificatie

UiterlijkUiterlijk Helder en kleurloze vloeistofHelder en kleurloze vloeistof JaJa

pHpH 5 5 –– 88 JaJa

Radiochemische zuiverheid (Radiochemische zuiverheid (HPLCHPLC)) > 98 %> 98 % JaJa

Specifieke Activiteit (ART)Specifieke Activiteit (ART) > 18,5 > 18,5 GBqGBq//µµmolmol NeeNee

Steriel en Steriel en pyrogeenvrijpyrogeenvrij BubblepointBubblepoint steriel filter > 1 barsteriel filter > 1 bar JaJa

AcetonAceton < 50 ppm< 50 ppm NeeNee

AcetonitrilAcetonitril < 50 ppm< 50 ppm NeeNee

TetrahydrofuraanTetrahydrofuraan < 50 ppm< 50 ppm NeeNee

TetrabutylammoniumhydroxideTetrabutylammoniumhydroxide < 50 ppm< 50 ppm NeeNee

DimethylformamideDimethylformamide < 50 ppm< 50 ppm NeeNee

Ethanol concentratieEthanol concentratie 5 5 –– 8 %8 % NeeNee

HalfwaardetijdHalfwaardetijd 18 18 -- 22 minuten22 minuten NeeNee

SteriliteitSteriliteit SterielSteriel NeeNee

BacterieleBacteriele endotoxineendotoxine gehaltegehalte < 2,5 EU/ml (< 2,5 EU/ml (VVmaxmax = 70 ml)= 70 ml) NeeNee

RadionuclidischeRadionuclidische zuiverheidzuiverheid > 99.9%> 99.9% NeeNee

RadionucliodischeRadionucliodische Identiteit Identiteit dmvdmvgammaspectrumgammaspectrum

0.511 0.511 MeVMeV NeeNee

Radiochemische identiteit Radiochemische identiteit RRtt = 4 = 4 -- 6 min (6 min (HPLCHPLC)) NeeNee

Chemische zuiverheidChemische zuiverheid Precursor < 0,1 Precursor < 0,1 µµMM ((HPLCHPLC)) NeeNee

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LogisticsLogistics [[1111C]Flumazenil PET C]Flumazenil PET studystudyHospital ProductionHospital Production

Prepare labPrepare labPatient arrivesPatient arrives

Prepare patientPrepare patient

Transmission scanTransmission scanReleaseRelease

InjectionInjectionBlood samplesBlood samples

Analysis blood samplesAnalysis blood samples

PreparationsPreparationsIsotope productionIsotope productionSynthesisSynthesisPurificationPurificationFormulationFormulationTransportTransportAnalysisAnalysis

08:3008:30

12:3012:3011:4511:4510:4510:4510:4010:4010:3010:3010:2510:2510:1510:1510:0010:0009:1509:15

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ConclusionConclusion

Basics of:Basics of:

nuclear imagingnuclear imagingCyclotron pridcution of radio isotopesCyclotron pridcution of radio isotopesPET radiochemistry PET radiochemistry 1111C, C, 1818F and F and 8989ZrZrGMP productionGMP production

Some examplesSome examples

Date post:	11-May-2018
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