positron emission tomography basics - mntp - university of

Positron Emission Tomography Basics: Radiochemistry

N. Scott Mason, Ph.D.

Radiochemist University of Pittsburgh PET Facility

University of Pittsburgh Department of Radiology

POSITRON EMISSION TOMOGRAPHY FACILITY

What is PET? Positron Emission Tomography

–  In-Vivo Imaging and Quantification of

Organ/Tissue Function – Uses Positron-Emitting Radiolabeled

Tracers



1. Cyclotron

2. Radionuclide

3. Radiosynthesis

4. PET Imaging

5. Image Reconstruction

6. Data Analysis

PET Imaging



Cyclotron



Positron Emitting Radionuclides

•  Atoms that can be included in amino acids, carbohydrates, steroids, water, other small molecules, etc. (F is isostere for H)

•  Short half-life: maximizes SNR to

subject radiation dose, but also means the isotope must be produced locally (18F can be shipped)

Half-life (min)"18F 109!11C 20!13N 10!15O !2!



Radionuclide Production Stable Nuclide!

18O!

Cyclotron!

Unstable Radionuclide!

18F!

n!

11 MeV protons!



Radionuclide Production 15N2

H216O

14N2 + O2

H218O

15O2

11CO2

13NH3

H18F

p,n

p,α

p,α

p,n



Potential C-11 Chemistry

(CH3)211CO

R11CO2MgBr

R11CO2H

11CH3NO2

H11CHO

11CH3OTf

R11COCl

R11CH2OH

11CO2

11CH3I

11CH3Li

11CH3OH

R11CHO

R11CONH2R11CONHRR11CONR2

R11CH2I



C-11 Carboxylation Chemistry

(CH3)211CO

R11CO2MgBr

R11CO2H

11CH3NO2

H11CHO

11CH3OTf

R11COCl

R11CH2OH

11CO2

11CH3I

11CH3Li

11CH3OH

R11CHO


R11CH2I



[C-11]WAY100635

N

NN

O

N

OMe **

Two potential labeling sites



[C-11]carbonyl WAY 100635

MgClO-

O

Cl

O

N

NN

O

N

OMe

N

NNH

N

OMe

*

*

*

+

[C-11]carbonyl WAY100635

[C-11]CO2



C-11 Methylation

(CH3)211CO

R11CO2MgBr

R11CO2H

11CH3NO2

H11CHO

11CH3OTf

R11COCl

R11CH2OH

11CO2

11CH3I

11CH3Li

11CH3OH

R11CHO


R11CH2I



[C-11]MeI System



[C-11]MeI System

[11C]Methyl Iodide System



[C-11]β-CFT chemistry

HNCOOCH3

F

NCOOCH3

F

H311C

100 µL acetone[C-11]CH3OTf

2 min @ 60 oCHPLC purification



[C-11]β-CFT microPET Imaging of Simian Unilateral MPTP Lesion Model

of Parkinson’s Disease

Intact Striatum

Lesioned Striatum

•  MPTP associated toxicity resulted in ~90% loss of DAT sites in left striatum as determined by PET



Dopamine D2/D3 Imaging: [C-11]FLB457

Br OMe

OH

HNO

N

Br OMe

O11CH3

HNO

N[11C]CH3OTf

NaOH

Acetone



Dopamine D2/D3 Imaging: [C-11]FLB457

•  Specific Activity Concerns – Ratio of radioactivity to cold mass – Expressed as Ci/mmole

•  Theoretical 9.4 x 106

•  Routinely achieved 2 x 103

– Minimize cold mass associated with radioactivity administration (0.6 µg)

– Atmospheric CO2 acts to decrease specific activity



[C-11]Pittsburgh Compound B [C-11]PIB

N

SHONH2

N

SHONH

11CH3[11C]CH3OTfMethyl Ethyl Ketone

6-HO-BTA-0 [11C]6-HO-BTA-1



[C-11]PIB Images

Examples of Pittsburgh Compound-B (PIB) Logan DVR images for a control , a ‘control-like’ mild cognitive impairment (MCI-2), an ‘AD-like’ MCI (MCI-4), and the AD (AD-1) subject with highest PIB retention.



F-18 Fluoride

•  Alkyl nucleophilic substitution (SN2)

•  Aromatic nucleophilic substitution (SN2Ar)

•  Issues –  Cation exchange and relatively anhydrous conditions



[F-18]FDG chemistry

O OAc

OTf

OAc

AcOOAc

O

OH

HOOH

18F

1. K[18F], K222

2. HCl

OH



[F-18]FDG chemistry



[F-18]FLT chemistry

N

NO

O

ODMTrO

HN

NO

O

OHO

18F

1. K[18F], K222, DMSO

2. HCl



[F-18]FLT uptake in mice bearing xenografted SCCHN tumors

tumors

brain



Metabolite Contribution

N

HN S

O

N

18F

O

HN

18F

O

N

HN S

O

N

18F

[F-18]Altanserin

[F-18]Altanserinol

[F-18]4-(4-Fluorobenzoyl)piperidine

HO H



Radiosynthesis of F-18]Altanserinol

N

HN

N NO2

OS

O

N

HN

N 18F

OS

OEtOHNaBH4

N

HN

N 18F

S

O

H OH

K18FDMSOhv



3’-[F-18]F-6-OH-BTA-1 Radiochemistry

36.54%

20.92%

12.03% 4.00%

N

S

18F

NHCH3

HO

N

SNO2

NCH3

O Pr1Pr2

[F-18]3'F-PiB

Precursors



3’-[F-18]F-6-OH-BTA-1 Semi-Preparative HPLC

36.54%

20.92%

12.03% 4.00%

Prodigy ODS-Prep 10 x 250 mm, 3/1/6 MeCN/ MeOH/ TEA Buffer, 1 mL/min 0-5min, 5 mL/min 5-10 min, then 8mL/min



3’-[F-18]F-6-OH-BTA-1 Final Product QC

36.54%

20.92%

12.03% 4.00%

Prodigy ODS-3 5µ 4.6 x 250 mm, 40% MeCN / 60% TEA Buffer, 2.0 mL/min



The Regional Distribution of [18F]3’F-PiB in AD Brain is Very Similar to that of [11C]PiB



Radiopharmacy Quality Control

•  Visual •  pH •  T1/2 determination •  Radiochemical Identity •  Radiochemical Purity •  Chemical Purity (Specific Activity) •  Residual Volatile Organic Solvent •  Endotoxin Testing •  Sterility



Acknowledgments

Chemists Scott Mason Steve Kendro Nicole DeBlasio April Radelet Guo-feng Huang

Physicists Julie Price Brian Lopresti Chip Laymon Eoin Carney Technologists James Ruszkiewicz Denise Ratica

Collaborators Raj Narendran Clayton Wiley Bill Klunk Jerry Schatten Jennifer Grandis

Funding: NIA, NIMH, NCI, NCRR, UPMC

Chester A. Mathis, Ph.D. - Director

positron emission tomography basics - mntp - university of

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