Radiopharmaceuticals

Definition of a Radiopharmaceutical A radiopharmaceutical is a radioactive compound used for

the diagnosis and therapeutic treatment of human diseases.

In nuclear medicine nearly 95% of the radiopharmaceuticals are used for diagnostic purposes, while the rest are used for therapeutic treatment.

Radiopharmaceuticals usually have minimal pharmacologic effect, because in most cases they are used in tracer quantities.

Therapeutic radiopharmaceuticals can cause tissue damage by radiation.

Definition of a Radiopharmaceutical

Because they are administered to humans, they should be sterile and pyrogen free, and should undergo all quality control measures required of a conventional drug.

A radiopharmaceutical may be a radioactive element such as 133Xe, or a labeled compound such as 131I-iodinated proteins and 99mTc-labeled compounds.

Definition of a Radiopharmaceutical

•Although the term radiopharmaceutical is most commonly used, other terms such as radiotracer, radiodiagnostic agent, and tracer have been used by various groups.

• We shall use the term radiopharmaceutical throughout, although the term tracer will be used occasionally.

Definition of a Radiopharmaceutical

• Another point of interest is the deference between radiochemicals and radiopharmaceuticals.

• The former are not usable for administration to humans due to the possible lack of sterility and nonpyrogenicity.

• On the other hand, radiopharmaceuticals are sterile and nonpyrogenic and can be administered safely to humans.

Definition of a Radiopharmaceutical

A radiopharmaceutical has two components: a radionuclide and a pharmaceutical.

The usefulness of a radiopharmaceutical is dictated by the characteristics of these two components.

In designing a radiopharmaceutical, a pharmaceutical is first chosen on the basis of its preferential localization in a given organ or its participation in the physiologic function of the organ.

Definition of a Radiopharmaceutical

Then a suitable radionuclide is tagged onto the chosen pharmaceutical such that after administration of the radiopharmaceutical, radiations emitted from it are detected by a radiation detector.

Thus, the morphologic structure or the physiologic function of the organ can be assessed. The pharmaceutical of choice should be safe and nontoxic for human administration.

Definition of a Radiopharmaceutical

• Radiations from the radionuclide of choice should be easily detected by nuclear instruments, and the radiation dose to the patient should be minimal.

IDEAL RADIOPHARMACEUTICAL

Ideal Radiopharmaceutical

• Since radiopharmaceuticals are administered to humans, and because there are several limitations on the detection of radiations by currently available instruments, radiopharmaceuticals should possess some important characteristics.

• The ideal characteristics for radiopharmaceuticals are:

Ideal radiopharmaceutical

• Easy availability• Short effective Half-Life• Minimal Particle Emission• Decay by Electron Capture or Isomeric

Transition• High Target-to Non target Activity Ratio

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1. Easy Availability

The radiopharmaceutical should be easily produced, inexpensive, and readily available in any nuclear medicine facility

Complicated methods of production of radionuclides or labeled compounds increase the cost of the radiopharmaceutical.

The geographic distance between the user and the supplier also limits the availability of short-lived radiopharmaceuticals.

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2. Short Effective Half-Life

A radionuclide decays with a definite half-life, which is called the physical half-life, denoted Tp (or t1/2).

The physical half-life is independent of any physicochemical condition and is characteristic for a given radionuclide

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2. Short Effective Half-Life (cont,..)

• Radiopharmaceuticals administered to humans disappear from the biological system through fecal or urinary excretion, perspiration, or other mechanisms.

• This biologic disappearance of a radiopharmaceutical follows an exponential law similar to that of radionuclide decay.

• Thus, every radiopharmaceutical has a biologic half-life (Tb).

• It is the time needed for half of the radiopharmaceutical to disappear from the biologic system and therefore is related to a decay constant, =0.693/Tb.

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2. Short Effective Half-Life (cont,..)

Obviously, in any biologic system, the loss of a radiopharmaceutical is due to both the physical decay of the radionuclide and the biologic elimination of the radiopharmaceutical.

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2. Short Effective Half-Life (cont,..)

• The net or e¤ective rate (le) of the loss of radioactivity is then related to the physical decay constant lp and the biologic decay constant lb. Mathematically, this is expressed as:

• λe = λp + λbSince λ = 0.693/t1/2, it follows that• 1/Te = 1/Tp + 1/TbOR

• Te = ( Tp X Tb) / ( Tp + Tb )

Problem :The physical half-life of 111In is 67 hr and the biologic half-life of 111In-DTPAused for measurement of the glomerular filtration rate is 1.5 hr. What is the effective half-life of 111In-DTPA?AnswerUsing Eq. Te = ( Tp X Tb) / ( Tp + Tb )Te = 1.46 h

Particle Emission

Radionuclides decaying by alpha- or beta-particle emission should not be used as the label in diagnostic radiopharmaceuticals. These particles cause more radiation damage to the tissue than do gamma rays. Although gamma-ray emission is preferable, many b-emitting radionuclides, such as 131I-iodinated compounds, are often used for clinical studies. However, alpha emitters should never be used for in vivo diagnostic studies because they give a high radiation dose to the patient. But alpha and beta emitters are useful for therapy, because of the effective radiation damage to abnormal cells

High Target-to-Non target Activity Ratio:

For any diagnostic study, it is desirable that the radiopharmaceutical be localized preferentially in the organ under study since the activity from nontarget areas can obscure the structural details of the picture of the target organ. Therefore, the target-to-non target activity ratio should be large.An ideal radiopharmaceutical should have all the above characteristics to provide maximum efficacy in the diagnosis of diseases and a minimum radiation

Radiopharmaceuticals

• Radioactive element - 133Xe• Labeled compounds - 131I iodinated

proteins• 99mTc labeled compounds• [18F]FDG

Production of Radionuclides

• Reactor-Produced Radionuclides

• Cyclotron-Produced Radionuclides

Reactor-Produced Radionuclides

Iodine-131

Molybdenum-99

Iodine-131

I-131 decays with a half-life of 8.02 days with beta minus and gamma emissions. This nuclide of iodine has 78neutrons in its nucleus, while the only stable nuclide, 127I, has 74. On decaying, 131I most often (89% of the time) expends its 971 keV of decay energy by transforming into the stable 131Xe (Xenon) in two steps, with gamma decay following rapidly after beta decay:

+ 606 keV + 364 keV

Molybdenum-9999Mo can be obtained by the neutron activation (n,γ reaction) of 98Mo in a high neutron flux reactor. However, the most frequently used method is through fission of uranium-235 in a nuclear reactor. While most reactors currently engaged in 99Mo production use highly enriched Uranium-235 targets

Molybdenum-99

99Mo has a half-life of 66 hours[1] and can be easily transported over long distances to hospitals where its decay product technetium-99m (with a half-life of only 6 hours, inconvenient for transport) is extracted and used for a variety ofnuclear medicine diagnostic procedures, where its short half-life is very useful.

Technetium-99m

• Technetium-99m is a metastable nuclear isomer of technetium-99, symbolized as 99mTc, that is used in tens of thosunds of medical diagnostic procedures annually, making it the most commonly used medical radioisotope.

Technetium-99m

• Technetium-99m when used as a radioactive tracer can be detected in the body by medical equipment (gamma cameras). It is well suited to the role because it emits readily detectable 140 keV gamma rays

• The "short" physical half-life (6h)of the isotope and its biological half-life of 1 day (in terms of human activity and metabolism) allows for scanning procedures which collect data rapidly but keep total patient radiation exposure low. The same characteristics make the isotope suitable only for diagnostic but never therapeutic use.

Cyclotron-Produced Radionuclides

. Fluorine-18 is used primarily to label glucose to give 18F-labeled fluorodeoxyglucose (FDG) formyocardial and cerebral metabolic studies. It is also used to label manypotential ligands for a variety of tumors and recently approved by the U.S.Food and Drug Administration (FDA) for bone imaging

Fluorine-18

Fluorine-18 (t1=2) 110 min is commonly produced by the 18O(p; n)F18reaction on a pressurized 18O-water target

Fluorine-18

Iodine-123

Iodine-123 is very useful in nuclear medicine because it has good radiationcharacteristics such as decay by electron capture, half-life of 13.2 hr and gamma rayemission of 159 keV. It is produced directly or indirectly in a cyclotronby several nuclear reactions.

Another important method of producing pure 123I is by the 124Xe(p; 2n) 123Cs reaction, in which case 123Cs(t0.5:5.9 min) decays to 123Xe. The124Xe gas is contained under pressure in a chamber and the chamber is irradiated with protons. Sufficient time is allowed for 123Cs to decay completely to 123Xe, which is then decays with a half-life of 2.1 hr to produce 123I. Iodine-123 decays by electron capture, half-life of 13.2 hr and gamma ray emission of 159 keV.

Kinetics of radioactive decayRadioactive decay equations

Decay rate:- Is the time rate at which atoms undergo radioactive disintegration.

- Radionuclides are unstable and decay by particle emission, electron capture or gamma ray emission.

- The decay of radionuclides is a random process. i.e. one cannot tell which atom from a group of atoms will decay at a specific time.

- The average number of radionuclides disintegrating during a period of time. The number of disintegrations/unit time = disintegration rate. = -dN/dt-dN: The change in the number of atoms, N. dt : The change in the time, t.

Radioactive decay is a first order process

- dN/dt of radionuclide at any time is proportional to the total number of radionuclides present at thet time.

- dN/dt (D) = λN where N is the number of radionuclides and λ is a decay constant that is defined as the probability of disintegration per unit time for a

single radionuclide. - dN/dt (D) radioactivity or simply the activity of a radionuclide .

dN

dtN

dN

N t

N N0e t

Rearrange:

Where N0 and Nt are the number of radionuclides present at t = 0 and time t, respectively.

"e" is the base of natural logarithm = 2.71828

If we remember the basic equation relating activity to number of nuclei in a sample, A=N, then we can write t

t eAA 0

tA

ALn t

0

Plot of radioactivity versus time on a linear graph. The time is plotted in units of half-life.

Plot of the data in the previous figure on a semi logarithmic graph, showing a straight-line relationship.

From the knowledge of the decay constant and radioactivity of a radionuclide, D=λN we can calculate the total number of atoms or the total mass of

radionuclide present using Avogadro’s number, 1gram-atom = 6.02 × 1023 atoms.

numbermass

massnumberAvogadrosnucleiofnumberN

Units of radioactivity:Radioactivity is expressed in units called curies.

1 curie (Ci) = 3.7 × 1010 disintegration per second (dps)

1 millicurie (mCi) = 3.7 × 107 disintegration per second (dps)

1 microcurie (μCi) = 3.7 × 104 dps

The other unit for radioactivity is becquerel (Bq) which is defined as one disintegration per second. Thus 1 becquerel (Bq) = 1 dps = 2.7 ×10-11 Ci

1 megabecquerel (MBq) = 106 dps = 2.7 × 10-5 Ci

Similarly, 1mCi = 3.7× 107 Bq = 37 MBq

Half-life and mean life:

Every radionuclide is characterized by a half-life, which is defined as the time required to reduce its initial disintegration rate or activity to one-half.

It is usually donated by t1/2 and is unique for a given radionuclide. The decay constant λ of a radionuclide is related to half-life by

2/12/1 44.1

693.0

1t

t

Another relevant quantity of a radionuclide is its mean life, which is the average life of a group of the radionuclides. It is donated by τ and related to decay constant λ and half-life tt1/21/2 as follows:

In one mean life, the activity of radionuclide is reduced to 37% of the initial value.

2/1

693.0

t

The physical half-life of 131I is 8.0 days.A. A sample of 131I has a mass of 100 μg. How many 131I atoms are present in

the sample?Number of atoms N

= 4.6 × 1017atoms

B. How many 131 I atoms remain after 20 days have elapsed?Nt= N0e−(λt)

= (4.6 × 1017 atoms)e−(0.693/8 d)(20 d)= 8.1 × 1016 atoms

C. What is the activity of the sample after 20 days?A or D = λN

= (0.693/8.0 d)(1/86400 s/d)(8.1 × 1016 atoms)= 8.2 × 1010 atoms/sec

= 8.2 × 104 MBq

massatomicgg

massatomicgatomsg

/131

)/1002.6)(10100( 236

D. What activity should be ordered at 8 AM Monday to provide an activity of 8.2 × 104 MBq at 8 AM on the following Friday?

Elapsed time = 4 daysAt = A0e−λt

8.2 × 104 MBq = A0e−(0.693/8d)(4d)8.2 × 104 MBq = A0(0.7072)

A0 = 11.6 × 104 MBq must be ordered

Problem:

Calculate the total number of atoms and total mass of 131I present in 5 mCi (185 MBq) 131I (t1/2 = 8 days).

Answer:λ for 131I =

16- sec101.0 6060248

693.0

atoms 10 1.85 10 1

10 1.85 14

6-

8

D

N

23

14

1002.6

1311085.1

D = 5 × 3.7 × 107= 1.85 × 108 dps

Using the equation

Since 1 g. atom 131I = 131 g

131I = 6.02 × 1023 atoms of 131I (Avogadro’s number),

Mass of 131I in 5 mCi (185 MBq) =

= 40.3 × 10-9 g

= 40.3 ng

Therefore, 5 mCi 131I contains 1.85 × 1014 atoms and 40.3 ng 131I.

Important Factors in Labeling

Shelf Life A labeled compound has a shelf life during which it can be

used safely for its intended purpose.

The loss of efficacy of a labeled compound over a period of time may result from radiolysis and depends on the physical half-life of the radionuclide, the solvent, any additive, the labeled molecule, the nature of emitted radiations, and the nature of the chemical bond between the radionuclide and the molecule.

Usually a period of three physical half-lives or a maximum of 6 months is suggested as the limit for the shelf life of a labeled compound.

The shelf-life of 99mTc-labeled compounds varies between 0.5 and 18 hr, the most common value being 6 hr.