Physics of Positrons and Production of PET Tracers

Physics of Positrons

and Production of PET

Tracers

Tim Marshel R.T.

(R)(N)(CT)(MR)(NCT)(PET)(CNMT)

SNMTS Approved

MIVWIQI: PET Radiopharmaceuticals

45 Hr PET Registry Review Course

Reference Number: 028625

1.5 CEH’s

Program Objectives• Discuss the physics of positron

• Discuss the properties of positrons

• Discuss the physics of electron capture

• Discuss the application of PET Imaging

• Discuss the value of PET in clinical imaging

• Review the basic preparation of PET Radiopharmaceuticals

• Review the molecular structure of FDG

• Discuss the various PET Radiopharmaceuticals used for clinical applications.

• Review the cyclotron process of manufacturing various PET Radiopharmaceuticals

• Review C-11

• Review N-13

• Review O15

• Review F-18

• Discuss the synthesis process for manufacturing PET Radiopharmaceuticals

Positive beta particles (+),

known as positrons, may be

emitted from radioactive nuclei

which have too many protons,

i.e., those which are proton-rich.

What Is a Positron?

e+ = a positive electron = +

A positron is a positive electron

emitted from proton-rich

radioactive nuclei.

Properties of Positrons (+):

Charge: +1 (i.e., + 1.6 x 10-19 coul)

Mass: me (one electron mass)

SI and LET: relatively low compared

to alphas

Positrons are formed by the following

nuclear transformation:

p n + e+ +

proton neutro

n

positro

n

neutrino

A nuclear proton is converted into a neutron

(altering the N to P ratio) followed by the emission

of the + and the .

Energy Requirement for Positron

Emission

The parent radionuclei must have

at least 1.02 MeV available to

produce the positron.

If the parent nucleus

does not meet this

energy requirement,

positron emission

cannot occur.

Positron Interaction in Matter:

Positrons are anti-matter.

When a positron encounters its

anti-matter counterpart, an

electron, annihilation radiation

results.

Annihilation radiation refers to

the disappearance of the

electron-positron pair and, in

their place, two 511 keV photons

that travel out in opposite

directions.

Annihilation Radiation

positronelectro

n511 keV

photon

511 keV

photon

With a positron emitter, one

shields against the

annihilation radiation, not the

positrons.

Best

Shielding: Sufficiently thick lead

Positron Decay Equation:

XAZ

YA

Z-1+ + + 0

10

parent daughter positron neutrino

Example:

F18

9O

18+ + + 0

0

1

0

0

8

Biologically Useful Positron Emitters:

Isotope Physical Half-Life

C 20.4 min11

N 9.96 min13

O 2.04 min15

F 1.83 hrs18

What happens to those

unstable nuclei that are

proton-rich but cannot meet

the energy requirement for +

emission?

The low-energy alternative decay

mode is

Electron Capture

Designated by EC or

When an unstable nucleus

decays by EC, an inner shell

electron is captured by the

unstable nucleus.

Its neutron to proton ratio is

adjusted through the

following transformation

Electron Capture

Characteristic

X-rays

Captured

Inner Shell

Electron

p + e n +

proton capture

delectro

n

neutron neutrin

oThe nucleus loses a proton but gains a

neutron. Only the neutrino is emitted from

the unstable nucleus.

Electron Capture Transformation:

If only the highly penetrating

neutrino in emitted from the

nucleus during electron capture,

what radiation is detected?

Characteristic X-rays!

Produced as a result of the

inner shell vacancy when the

electron was captured.

Electron Capture Decay Equation:

XAZ

+ e 0-1

YAZ-1

+ 00

Example:

I12553

+ e-10

Te

52

125 + 0

0

parent captured

electrondaughter neutrino

Radionuclides That Decay by

Positron Emission or ECRadionuclide Decay Mode Half-Life

111In EC (100%) 2.83d

125I EC (100%) 60d

15O + (100%) 2.04

m18F + (97%)EC (3%)

1.83 h

Important Note:

Proton-rich nuclei may decay

either by• electron capture only

,• positron emission only,

or• either EC or positron

emissiondepending upon the specific radionuclide

What is PET?

"PET" stands for Positron Emission Tomography. This technique allows us to measure organ function while the patient is comfortable, conscious and alert.

What is PET?

PET represents a new step forward in evaluating function of internal organs and in diagnosing malignant tumors. Unlike X-rays or a CT scan, which show only structural details within the body, PET excels at determining organ function.

What is PET?

We are very interested in organ function because functional change often predates structural change in tissues, such as tissue metabolism and physiologic functions.

What is PET?

• In oncology, PET is the only modality that can accurately image many organs of the body with a single pass to allow determination of malignancy.

• PET helps determine whether a primary cancer has metastasized to other parts of the body.

Value of PET

• permits cost effective, whole-body metastatic surveys

• avoids biopsies for low grade tumors

• permits non-invasive differentiation of tumors from radiation necrosis

• permits early change in course of ineffective chemotherapy

• avoids unnecessary diagnostic and therapeutic surgeries.

PET Radiopharmaceuticals

• PET radiopharmaceuticals commonly incorporate short-lived radionuclides of elements encountered in nature, e.g.,

15O (t1/2 = 2 min), 13N (t1/2 = 10 min),11C (t1/2 = 20 min), 18F (t1/2 = 110 min).


• produce no physiological or pharmacological effects; inherently have a high degree of safety.

• No documented adverse reactions of clinical significance after tens of thousands of studies performed in humans worldwide


• radiation exposure from a PET imaging procedure is comparable to that of other Nuclear Medicine diagnostic procedures using gamma-emitting radiopharmaceuticals, many of which have been in use for decades.

PET Radiopharmaceuticals:

Underlying Principle

the radioactive substance used to evaluate the metabolic or physiologic process must not alter the process it is attempting to measure.


compounds are generally chemically equivalent or close analogs to naturally occurring compounds

provide functional images of the human body.


Many PET radiopharmaceuticals are radiolabeled versions of substances commonly present in the body, e.g., 13N-ammonia, 15O-water, 11C-acetate, 11C-methionine, 18F-fluoride.


• The most widely used PET radiopharmaceutical is 18F-FDG. Similar in structure to glucose, this compound is used in PET due to the ubiquitous use of glucose by the human body.


• FDG is labeled with 18F, a cyclotron produced radioisotope with a half life of approximately 110 minutes.

Preparation of 18F-FDG 1. synthesis is based on the nucleophilic substitution with 18F

-, promoted by a

phase transfer catalyst.

2. The process includes the separation of the 18O from the 18F, labeling reaction, hydrolysis and finally formulation as an injectable solution.

Preparation of 18F-FDG

3. process time is < 30 min.

4. the radiochemical yield is 50 to 60 % depending on purity of starting material

5. the specific activity is >10 Ci/µmol (370 GBq/µmol)

6. the radiochemical purity is > 98.5 %.

Comparison: Structures of FDG

and Glucose

HO

OH

OH

OH

OH

OCH2OH

OH

18F-FDG d-Glucose

O

OH

18F

HO

18F-FDG: Mechanism of Uptake

Called metabolic trapping

Tumors have higher metabolic rate than normal tissue.

Structures of FDG and glucose are similar enough for there to be uptake, but different enough that metabolism can not take place.

PET Radiopharmaceuticals: 11C Compounds

• CO• Raclopride• N-methylspiroperidol• hydroxyephedrine• acetate• L-deprenyl• L-methionine• thymidine• flumazenil

PET Radiopharmaceuticals: 13N, 15O Compounds

• 13N-ammonia

• 15O-water

• 15O-butanol

PET Radiopharmaceuticals: 18F Compounds

• fluoride• FDG• 6-fluoroDOPA• fluoromethane• N-methylspiroperidol• 6-fluoronorepinephrine• 14-fluoro-6-thiaheptadecanoate• 16-fluoro-17b-estradiol• fluoroethyl-oubain• fluoromisonidazole

PET Radiopharmaceuticals:

Other Compounds

• 82Rb+ ion

• 68Ga-EDTA

• 62Cu-PTSM

• 76Br-bromolisuride

• 124I-monoclonal antibody

PET Reimbursement Issues

FDA and Medicare approval of the radiopharmaceuticals used in PET has always been a prerequisite for public-sector reimbursement.

PET Pharmaceuticals:

Clinical Utility

Most commonly used in oncology to detect and evaluate tumors

useful in cardiology to assess myocardial viability

also useful in the brain for diagnosis of a variety of neurological conditions

General Tumor Imaging with FDG

FDG-PET is effective in the diagnosis and staging of the following cancers: brain tumor, breast cancer, colorectal cancer, head and neck cancer, lung cancer, lymphoma, melanoma, musculoskeletal tumors, ovarian cancer, pancreatic cancer, and thyroid cancer.

Approved indications for

whole-body 18F-FDG PET scans

• evaluation of recurrent colorectal Ca in patients with rising CEA levels

• staging and characterization of lymphoma (both Hodgkin's and non-Hodgkin's lymphoma, when performed as an alternative to a gallium scan)

• detection of recurrent or metastatic melanoma prior to surgery


whole-body 18F-FDG PET scans

• Characterization of solitary pulmonary nodules

• Initial staging of non-small cell lung cancer


cardiac 18F-FDG PET scans

CPT CODE Indication

78459 Cardiac metabolism

78499 Cardiac perfusion

78990 Radiopharmaceutical

PET in CardiologyCardiology enables physicians to:

• screen for coronary artery disease

• assess flow rates and flow reserve

• distinguish viable from nonviable myocardium for bypass and transplant candidates.


cerebral 18F-FDG PET scans

CPT CODE Indication

78608 Brain metabolism

78609 Brain perfusion

78990 Radiopharmaceutical

PET in Neurology

• PET enables assessment of Alzheimer’s and other dementias, Parkinson’s, and Huntington’s

• Localizes epileptic foci for qualifying and identifying the site for surgical intervention

• Permits characterization, grading, and assessment of possible brain tumor recurrence

Lets look at the

cyclotron

manufacturing

process more

closely….

Hot Cells

• 6 hot cells SMC1 and SMC2/70

• 1 laminar shielded box NMC1/70

• 1 shielded isolator DMC3/75

(TEMA Sinergie)

Synthesis modules

• TRACERlab FXFDG

• TRACERlab MXFDG

• TRACERlab FXDOPA

• TRACERlab FXC

• NH3 module IBA

PET radionuclides

Nuclide T1/2

[min]

Target Reaction Pharmaceutical

18F- 11O [18O]H2O 18O(p,n) FDG and NaF

18F2 110 Ne + F2 20Ne(d,) DOPA

13N 10 H2O 16O(p,) NH3

11C 20 N2 + O2 14N(p,) CH3I raclopride

15O 2 N2 + O2 14N(d,n) H2O


Radiopharmaceutical

Applications

[18F]-Fluorodeoxyglucose

(FDG)

glucose metabolism in tumours,

myocardium and brain, Alzheimer disease

L-3,4-Dihydroxy-6-[18F]-

fluorophenylalanine (DOPA)

aminoacids transport in brain and tumours,

Parkinson‗s disease

[18F]-Fluoride sceleton

[11C]-Raclopride dopamine receptor ligand

[15O]-Water myocardial blood flow

[13N]-Ammonia regional blood flow

Preparation of radiopaharmaceuticals

• 13N and 15O radiochemical syntheses – limited to one reaction step by half-life of radionuclide. 15O-labeled radiopharmaceuticals: water, butanol and gases for inhalation studies (CO, CO2)13N-labeled radiopharmaceuticlas: nitrite/nitrate and ammonia.

• 11C and 18F radiochemical syntheses – many synthetic routes to prepare PET radiopharmaceuticals11C-methylation, 18F— -nucleophilic substitution, 18F2 –electrophilic substitution: large variety of biologically active compounds can be prepared.

Radiochemistry with 18F

FDG – nucleophilic substitution

Step TRACERLAB MXFDG TRACERLAB FXFDG

18F separation Anion exchange column

Elution K2CO3 + Kryptofix 2.2.2.

K18F

TBAH CO3

TBA18F

Nucleophilic

substitution

Hydrolysis NaOH, H2O, r.t. HCl, H2O, 125°C

Chromatographic

separation

1x C18 SepPak cartridge,

1x alumina N cartridge

1x cation exch. cartridge,

2x anion exch. cart.,

1x aluminium oxide cartr.,

1x reversed phase cartr.

DOPA – electrophilic substitution

Step Reaction

18F2 trapping precursor solution in freon-11

Electrophilic substitution

Hydrolysis

Chromatographic

separation

Chromatographic column: Nucleosil 100 C-18 HD,

5m, 16x250 mm

Eluens: 2% ethanol in 0,05M NaH2PO4

Flow: 8 ml/min

Radiochemistry with 11C

• The most commonly used C-11 precursor is methyl iodide.

• There are two common ways to prepare [11C]methyl iodide: ―wet‖ method and the ―gas phase‖ method

• ―wet‖ method – reduction of to 11CO2 to [11C]methanol by LiAlH4, followed by treatment with HI

• ―Gas phase‖ method – using iodine vapor and 11CH4

C-11 methylation

Step Reaction

11CO2 convertion into 11CH4 Online by Ni-catalytist support under continous addition

of hydrogen at 400oC

Purification and concentration Produced 11CH4 – trapped on Carbosphere at -140 oC

Circulating process 11CH4 reaction with iodine at 720 oC to form

[11C]methyliodide

Trapping HI – trapped by Ascarite trapp

Formed [11C]methyliodide – trapped by Porapak Q at r.t.

Unconverted 11CH4 – returns back into the circulating

process for reaction with I2

Step Reaction

[11C]methyliodide collection In the reaction vial in the precursor / solvent system

Labelling reaction The product is formed by nucleophilic exchange of

nucleophilic function of the precursor molecule against

iodine anion of the [11C]methyliodide.

Product separation To separate the reaction mixture containing the labelled

product radio-HPLC is performed. The product peak is

cut from the chromatographic system by valve switching

to the product line.

Solid phase extraction

purification

Is needed if the radio-HPLC mobile phase is not

injectable/applicable for patient treatment.

The purification is carried out on the C-18 Sep Pak

cartridge.

PET radiopharmaceuticals are different because:they are positron emitters have short physical half-lives;

Most common PET radionuclides are:C11, O15, N13,F18, Rb82

F18 is radionuclide of choice due to its relatively longer half-life of 110mins which allows it to supply to remote places.

Suitable synthesis method is adopted to provide a stable product with:Good labeling yieldHigh specific activityHigh purityHigh in vivo tissue selectivity

Half Life- 110minsProduced by irradiation of 18O-water with 10-18 MeV protons in a cyclotronpH should be between 4.5-8.0.F18- sodium fluoride is used for synthesis of F18-flourodeoxyglucose and for F18-labeled PET radiopharmaceuticals.Localizes in bone by exchanging with PO4 ion in the hydroxyapatite crystal

Produced in places where a cyclotron is locally availableF18-2-FDG is produced by electrophilic substitution with F18-fluorine gas or nucleophilic displacement with F18- fluoride ions.

Prepared by nucleophilic reaction between F18-sodium fluoride and a precursorF18-sodium fluoride is added to a mixture of Kryptofix and potassium carbonate in acetonitrile.Mixture is dried to residue by heating 120°C for 5mins.Precursor is added to dried residue and heated 160°C for 10 mins.Overall yield is 45%; radiochemical purity is >95%Synthesis time is 60 minutes.F18-FLT is commonly used for in vivo diagnosis and characterization of tumors in humans

Produced in places where there is a cyclotron availableMethods of synthesizing 6-F18-L-Fluorodopa is fluorodemetallation using electrophilic fluorinating agents.The L-isomer in dopa is important because the enzymes that convert dopa to dopamine, are targeted by the radiopharmaceutical, are selective for this isomer.F18-labeled acetylhypofluorite is prepared in the gas phase then allowed to react with the mercury precursors in chloroform or acetonitrile at room temperature.Used to asses presynaptic dopaminergic function of the brain.

Half life- 2mins Produced I cyclotron by the N15 O15 reaction, or N14 O15 reactionIrradiated gas id transferred to a O15 water generator and O15 mixes with hydrogen and passed over a palladium/charcoal catalyst at 170°C .H2 O15 is commonly used for myocardial and cerebral perfusion studies.

Prepared by reaction of O15-oxygenCarrier oxygen (concentration of 0.5%) is added to the N15 target to recover O15.O15-butanol is used for blood flow measurement in the brain and other organs.It’s a better perfusion agent then O15 water due to its partition coefficient of nearly 1.0 compared to 0.9 for water .

Half life- 10minsProduced by reduction of N13-labeled nitrates and nitrates produced by proton irradiation of water in a cyclotron.pH should be between 4.5- 7.5.FDA approved it for measurement of myocardial and cerebral perfusion.

Produced by reaction of Grignard reagent methylmanesium bromide in diethyl by cyclotron-produced C11-carbin dioxide at ambient temperature.After reduction, product is hydrolyzed with water or aqueous acid.C11-acetate if found to be stable at pH 4.5 -8.5 for up to 2hrs at room temp.Overall yield is 75%.Used for measurement of oxygen consumption in the heart.

Commonly labeled at the N-methyl position by N-methylation with C11-iodomethane.Prepared from C11-CO2 and use freshly prepared Grignard reagent, methylmagnesium bromide.Unstable for up to 3 hours at room temp. at pH 7.0.C11-Flumazenil is used for neuroreceptor characterization in humans

Prepared by N-methylation of commercially available spiperone with C11-methyl iodide in the presents of Grignard reagent using different solvents and bases.Cold spiperone present in preparation reduces its specific activity and should be controlled.Specific activity should be around 10- 50GBq/mol.pH is adjusted to 7± 1 with a suitable buffer.C11-methylspiperone is used to determine the dopamine-2 receptor density in pt with neurological disorders.

Has 2 forms:L-(1-C11)methionine and L-(S-methyl-C11)methionineFormer is obtained by:Reaction between C11-CO2 precursor and carbanion produced by strong base added to respective isonitrile, followed by hydrolysis with an acid.Product is purified by HPLC yielding purity of >98%pH is between 6.0- 8.0; stable at room temperature for 2 hoursUsed to detect different types of malignancies, reflecting the amino acid utilization.

Labeled with C11 by N-ethylation with 1-C11 iodoethane or O-methylation with 1-C11 iodomethane.C11-labeled iodoethane and iodomethane are prepared from C11-CO2.Product is purified by HPLC, purity >98%.pH is between 4.5- 8.5 and stable for more than 1 hour at room temperatureUsed to detect various neurological and psychiatric disorders, such as Parkinson’s disease and schizophrenia

Available from the Sr82-Rb82 generatorActivity in column is 90-150mCi Sr82 at calibration timeRb82 is eluted with saline and must be checked for Sr82 and Sr85 breakthrough dailyRb82 have a short half life of 75 secondsAdministered by infusion pumpRb82 is FDA approved for myocardial perfusion imaging to delineate ischemia from infarction.

Conventional methods of synthesis of radiopharmaceuticals using high level radioactivity are likely to provide high radiation exposure to the persons involvedTo minimize exposure levels, automated modules have been devised for synthesis of PET radiopharmaceuticals

Black box- is an automated synthesis deviceIt is a unit controlled by microprocessors and software programs to carry out physical and chemical steps to accomplish the entire synthesis of a radiolabeled product.

Unit consist of templates or pre-filled vials attached via tubing connected to switch so it may be turned off and on as needed.It is small and self-cleaning, may have used of cassettes to be used for each synthesis.

Synthesis Parameters include:Time, pressure , volume, and other requisites are controlled by remote computer

Unit has a graphic display showing status of on-going process.After synthesis, a report with date, start and end time of radiosynthesis, and calculated yield is printed out.

PET Radiopharmaceuticals must be tested for:•Chemical purity•Radionuclidic purity•Radiochemical purity•pH•Isotonicity•Sterility•Pyrogenicity•toxicity

PET Radiopharmaceuticals are short-lived, many test cannot be done before administration.

Dry Runs- QC test done on products without administration to patient

QC test are divided into:Physicochemical test and biological test.

Physical appearance- relates to the color, clarity or turbidity of a PET radiopharmaceutical; should be checked by visual inspection

pH- PET radiopharmaceutical for human administration should be 7.4Isotonicity- is the ionic strength of a solution, adjusted by adding appropriate electrolytes.

Radionuclidic Purity- is the fraction of total activity in the form of the desired radionuclide in the sample.

Chemical Purity- is the fraction of a radiopharmaceutical in the form of the desired chemical molecule whether all of it is radiolabeled or not.

Radiochemical Purity- is defined as the fraction of the total activity in the desired chemical form in the sample.

Sterility- indicates the absence of any viable bacteria or microorganisms in a radiopharmaceutical preparation.

Pyrogenicity- are polysaccharides or proteins produced by the metabolism of microorganisms, and upon administration, cause symptoms like fever, chill, sweating.

Toxicity- toxicity of a radiopharmaceutical causes alterations in the histology or physiologic functions of an organ or even death of a species after in vivo administration.

F18- fluorodeoxyglucose

Appearance: ClearpH: 4.5 – 7.5Specific Activity: not less than 1mCi/μmolRadionuclidic Purity: not less than 99.5%Chemical Purity: major impurities, Kryptofix 2.2.2 and 2-chloro-2-deoxy- D-glucoseRadiochemical Purity: determined by TLC using activated silica gel as the solid phase and mixture of acetonitile and water as the solvent.

6-F18-L-Fluorodopa

Appearance: ClearpH: 6 – 7Specific Activity: not less than 100 mCi/mmolRadionuclidic Purity: not less than 99.5%Chemical Purity: mercury is the major toxic impurity.Radiochemical Purity: determined by the HPLC method or ion pair chromatography.

N13-Ammonia

Appearance: ClearpH: 4.5 – 7.5Specific Activity: no carrier addedRadionuclidic Purity: not less than 99.5% should correspond to 511 keVChemical Purity: aluminum and titanium are common impurities, determined by colorimetric methodsRadiochemical Purity: determined by the HPLC method.

Physics of Positrons and Production of PET Tracers

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