Practical Aspect of Tc 99m radiopharmaceuticals

Practical Aspects of Tc-99m
Radiopharmaceuticals
Al Rowaily
Mohammed,MSc,CRP,PhD

Production of Radioisotopes
• Disturb the N/Z ratio
– Addition of neutrons
– Addition of charged particles such as protons (1H),
deuterons (2H), alpha particles (4He) etc.
– Fission of heavy elements such as 235U, 239Pu
• Isotopes are produced in a nuclear reactor or
in an accelerator such as cyclotron

Production of Radioisotopes
 
 C
  
  
     
N EUTR O N
D EFIC IEN T
IS O TO P E
N EUTR O N
R IC H
IS O TO P E
C harg ed
particleN eutron
C YC LO TR O NR EA C TO R
TA R G ET M A TER IA L

Production of Radioisotopes:
Nuclear Fission
Short lived- 99Mo, 131I, 133Xe
Long lived- 137Cs, 90Sr
FISSION PRODUCTS
Neutron
REACTOR
FISSILE MATERIAL
235U is bombarded with
neutrons
235U splits yielding two
elements and a 2-3
neutrons
There is one light and one
heavy element formed
during fission
90Sr, 99Mo
131I, 133Xe, 137Cs

The Missing Element#43
Brief History of Chemistry
Mohammed Al Rowaily

• By 4000 BCE, in Egypt and Sumeria
(Iraq), metals such as copper and gold
were being used.
• In addition to metallurgy Egypt also
developed embalming and dying
• The Greeks named this learning
Khemeia from Khumos, juice of plants
Chemistry from “Khemeia”

• Democritus
• 460 BCE to 370 BCE
• Believed that all matter is made
up of various imperishable,
indivisible elements
• He called these atoma (sg.
Atomon) or "indivisible units"
Ancient Greeks

Ancient Greeks
• Plato and Aristotle
• Aristotle (384 BCE to
332BCE)
• Believed there were 4 classic
elements
– Earth, fire, water, air

Robert Boyle
Developed the “scientific
method” where experiments
were devised to test theories.
Defined an ‘element’ as
something unable to be
broken down into simpler
substances. ~1660
1st true “chemist”
Discovered a relationship between pressure
and volume (Boyle’s Law)

Antoine Lavoisier
1743 (Paris) – 1794 (Paris)
“The Father of
Modern Chemistry”
Defined a chemical “element”
as a substance that cannot be
decomposed into simpler
substances by chemical means.
Created a table of 33 of
the then known elements.
Grouped the elements into four
categories based on their physical
and chemical properties. These
categories were gases, nonmetals,
metals, and earths.

Found that a given compound always contains
exactly the same proportion of elements by
mass - Law of Definite Proportions
Joseph Louis ProustHe discovered the law of definite proportions,
which states that every chemical compound
contains fixed and constant proportions by
weight of its constituent elements (law).
Proust worked with many chemical
compounds and still found that no matter
where the compound came from or how it was
produced, it had the same composition.
Joseph Louis Proust
September 26, 1754 – July 5,1826
a French chemist

1) all matter is composed of tiny particles
called atoms
2) the atoms of an element are always
identical while the atoms of different
elements are different
3) compounds form when atoms
combine; atoms combine in small whole
number ratios
4) reactions involve reorganization of
atoms; the atoms themselves do not
change
John Dalton
Atomic Theory

Jöns Jakob Berzelius
Developed a table of atomic weights
in 1828.
Introduced the use of letters as
symbols for the elements.
Determined the atomic weight of 43
elements.
First to isolate pure calcium, barium,
strontium, silicon, titanium, and
zirconium.
Discovered selenium, thorium, and
cesium.
Swedish chemist
1779 – 1848

Johann Döbereiner
In 1817, he proposed “triads,” or
groups of three elements with similar
properties. He later published these
ideas in 1829.
Examples of triads:
lithium, sodium, & potassium;
calcium, strontium, & barium;
chlorine, bromine, & iodine.
Discovered that the relative atomic
mass of the middle element in each
triad was close to the average of the
relative atomic masses of the other
two elements.
German Scientist
1780–1849

John Newlands
Proposed the “Law of Octaves.”
In 1863, he arranged the 62 known
elements in order of their atomic weights
and observed similarities between the first
and ninth and second and tenth elements,
etc.
H 1
Li 2
Be 3
B 4
C 5
N 6
O 7
F8
Na 9
Mg 10
Al 11
Si 12
P 13
S 14
Cl 15
K 16
Ca 17
Cr 19
Ti 18
Mn 20
Fe 21
Co & Ni 22
Cu 23
Zn 24
Y 25
In 26
As 27
Se 28
Br 29
Rb 30
Sr 31
Ce & La 33
Zr 32
Bi & Mo 34
Rh & Ru 35
Pd 36
Ag 37
Cd 38
U 40
Sn 39
Sb 41
Te 43
I 42
Cs 44
Ba & V 45
Ta 46
W 47
Nb 48
Au 49
Pt & Ir 50
Os 51
Hg 52
Tl 53
Pb 54
Bi 55
Th 56
1837 (London) – 1898 Newlands’ Periodic Table

Lothar Meyer
In 1869, he compiled a
periodic table of 56
elements based on the
“periodicity” of their
properties (e.g., molar
volumes) when
arranged in order of
increasing atomic
weight.
German chemist
1830 – 1895

Dmitri Mendeleev
“Father of the Modern
Periodic Table”
Russian Physicist and Chemist
1834 – 1907
Constructed a periodic table by
arranging elements:
•in order of increasing atomic mass
•in vertical groups based on similar
chemical properties
•He left gaps for undiscovered
elements and reversed the order of
some elements to make their
chemical properties fit.

From the 1860s through 1871, early forms of the
periodic table proposed by Dimitri Mendeleev
contained a gap between molybdenum
(element 42) and ruthenium (element 44).
In 1871, Mendeleev predicted this missing
element would occupy the empty place
below manganese and therefore have similar
chemical properties. Mendeleev gave it the
provisional name ekamanganese
Element-43

Some Trials
In 1877, the Russian chemist Serge Kern named it
davyum---- a mixture of iridium, rhodium and iron .
1908, the Japanese chemist Masataka Ogawa—
was rhenium

Some Trials
German chemists Walter Noddack, Otto
Berg, and Ida Tacke reported the discovery
of element 75 and element 43 in 1925, and
named element 43 masurium.
it was dismissed as an error for many years but is
still a debated as to whether the 1925 team actually
did discover element 43.
Ida Tacke

In The Way to Fill The Gap
EMILIO GINO SEGRÈ
1905 Tivoli, Italy –1989
California,USA
In the summer of 1936 Segrè and
his wife visited the United States,
first New York at Columbia
University, and then Berkeley at
Lawrence’s Radiation Laboratory.
He persuaded Lawrence to let him
take back to Palermo some
discarded cyclotron parts that
had become radioactive

He found that his samples contained
a variety of known radioactivities that had been deposited
on them from bombardment of different targets
In early 1937 Lawrence sent him a molybdenum foil that had been part
of the dflector in the cyclotron. For Segrè this was a godsend. The
atomic number of molybdenum is Z = 42
Back in Palermo

The foil had been bombarded with deuterons, a hydrogen
isotope of mass 2 consisting of a neutron and a proton. By
then (d, p)and (d, n) reactions were recognized, in which one
or the other of the projectile’s nucleons is captured by the
target nucleus. In the (d, n) process, the proton is captured to
create a nucleus with Z = 43.
Alternatively, the (d, p) process could lead to a radioactive
isotope of molybdenum that undergoes beta decay to produce
Z = 43.
Cont.,

Segrè enlisted his experienced chemist colleague Carlo Perrier
to attempt to prove through comparative chemistry that the
molybdenum activity was indeed Z=43, an element not
existent in nature because of its instability against nuclear
decay.
With difficulty they finally succeeded in isolating three
distinct decay period (90,80, and 50 days) that turned out to
be 95Tc and 97Tc, of technetium.
The name given later by Perrier and Segrè to the first man
made element
The Gap Officially filled “The discovery”

History of radiopharmaceuticals and radiopharmaceutical
chemistry
Technetium-99m radiopharmaceuticals
-
• Technetium-99m was introduced into nuclear medicine in 1957 with the
development of the 99Mo-99mTc generator at the Brookhaven National
Laboratory.
• First clinical use of 99mTc was in University of Chicago in 1961 to
provide nuclear medicine imaging procedures based mainly on continuous
availability and favorable physical properties: t1/2 of 6 hours, a 140-keV
photon (88% abundance) which provides good tissue penetration and
imaging capabilities (for use with gamma cameras) and no alpha or beta
decay, providing a low absorbed dose.

Technetium-99m generators
• technetium-99m generators commercially available from
1963 on and from then preparation of 99mTc-
radiopharmaceuticals in hospitals
• chemistry of 99mTc poorly understood till mid 70-ies; Tc-
complexes poorly characterized
• A. Jones and A. Davison (Boston) pioneers in Tc-complexation
chemistry
• Well characterized 99mTc-complexes in 80-ies and 90-ies:
99mTc-MAG3, -sestamibi, -MDP, HMPAO, -bicisate, -
tetrofosmin, -IDA dervatives (mebrofenin)

ERC_IEO (R. Pasqualini)
Oct 2009
99Mo / 99mTc generator: A rapid view to the 99Mo shortage
China
6 reactors in the world produce radiopharmaceutical
grade 99Mo
Courtesy of A. Alberman, CEA - France

First Generator
The original 99mTc
generator (shown without
shielding) ca. 1958

99Mo / 99mTc generator: basic technologies
• Basically, a 99mTc generator consists of a
chromatographic column containing alumina,
eluted by saline.
• 99Mo (as molybdate is strongly bound to the
alumina, whereas
99mTc (as pertechnetate) is loosely bound to
this phase.
• Chloride ions, from saline, elute pertechnetate
through a chasing mechanism.

ERC_IEO (R. Pasqualini)
Oct 2009
99Mo / 99mTc generator: basic chemistry
In principle, the 99Mo / 99mTc generator is based on a quite simple
chemistry:
One solid support made of positively charged alumina
+
+
+
+
Weakly negatively charged 99mTcO4
- ions, loosely bound to alumina
[99Mo7O24]6-
[99Mo7O24]6-
Highly negatively charged (99Mo7O24
6-) species, formed at acidic pH,
which firmly bind to alumina
[99Mo7O24]6-
[99mTcO4]-
[99mTcO4]-
99mTcO4
- (only) is stripped from alumina by eluting with saline
[99mTcO4]-
NaCl NaCl NaCl

99Mo / 99mTc generator: basic technology
• Basically, a 99mTc generator consists of a
chromatographic column containing alumina,
eluted by saline.
• 99Mo (as molybdate is strongly bound to the
alumina, whereas
99mTc (as pertechnetate) is loosely bound to
this phase.
• Chloride ions, from saline, elute pertechnetate
through a chasing mechanism.

99Mo / 99mTc generator: basic chemistry
Actually, the 99Mo / 99mTc generator is a complex system, mainly
because of the formation of highly reactive free radical species
(including hydrated electron) created by the high level of radioactivity
deposited in a small volume of the column.
Hydrated electron and free radicals may react with 99Mo and
99mTc generating new unwanted chemical species !
h
OH2
e- .HO + H
+
+
ionization
dissociation .HO H+ .

Why retention of 99mTc activity is higher when high specific activity (fission)
99Mo is used in place of low specific activity (reactor) 99Mo ?
High specific activity 99Mo Low specific activity 99Mo
Mo
99
Tc
99m
+ e-
e-
99m
+
Mo
99
Tc
99m
+ e-
Mo
99
Tc
Mo
99
Tc
99m
+ e-
Mo
99
+ e-
Mo
99
Tc
99m
+ e-
Mo
99
Tc
99m
+e-
Mo
99
Tc
99m
+e-
Mo
99
Tc
99m
+e-
Mo
99
Tc
99m
+e-
Mo
99
Tc99m+e-
Mo
99
Mo
99
Tc + e-
Mo
99
Mo
99
Mo
99
Tc
Mo
99
Mo
99
e-
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
Mo
99
 Fission 99Mo is at a much higher specific activity (1000 times more) than
“reactor” 99Mo. Therefor an alumina column will be loaded with µg amounts
of fission 99Mo and with mg amounts of reactor 99Mo.
99Mo fission is concentrated in few mm3 of alumina, so are pertechnetate
and the emitted electrons:
99Mo / 99mTc generator: eluting 99mTc

The mass of total technetium will depend on :
- 99Mo activity loaded on the column
- interval of time between two successive elutions
- elution yield
- The the ratio between 99mTc and 99Tc will depend on:
- interval of time between elutions and decay of 99mTc, once eluted
Example: the amount of total technetium in 10 GBq (270 mCi) of a 24-
hour interval eluted generator is approximately 0.2µg.
If a 96-hour interval between elutions had occurred, this amount would
have increased up to 1µg.(Activity & Specific Activity)
99Mo / 99mTc generator: in-growth 99mTc kinetics
Consideration on chemical / physical properties of 99mTc:

Activity and Specific activity
e.g. The longer the 99Mo/99mTc generator is not eluted,
the higher 99Tc content is formed, (due to the decay
of 99mTc), resulting in lower specific activity of 99mTc
Theoretical Sp.A. of carrier-free 99mTc = 195 GBq/g
Sp.A. of non-carrier added 99mTc vs time between elutions:
Time
between elutions 99mTc/99Tc Sp.A. 99mTc
6 hrs 1.5 : 1 117.2 GBq/g
24 hrs 1 : 2.6 53.4 GBq/g
72 hrs 1 : 12.6 14.6 GBq/g

Technetium-99m: the radionuclide of choice in
Nuclear Medicine
• Continuous availability from generator at reasonable
cost
• Half-life = 6.02 h
• low radiation dose to patients and operators because:
[ No alpha or beta radiation and limited number of low
energyAuger/conversion electrons[ gamma rays
(140.6 keV) can easily be shielded
• Ideal gamma-ray energy for Anger camera
• Transition metal easy formation of diversity of
complexes

Due to their short half-life, all 99mTc-radiopharmaceuticals are
prepared by the user just before administration to the patient.
The general reaction for the preparation of Tc-labeled
radiopharmaceuticals is:
[99mTcO4]- + reducing agent + L [99mTcLn]
This reaction is performed by using a kit, i.e. a vial(s)
containing sterile and pyrogen-free ingredients able to
yield the final product within a short time (5 to 30 min)
and in high radiochemical yield (> 95%)
Radiopharmaceutical Preparation with 99mTc: General

• To contain all ingredients for labelling, ensuring appropriate
labelling conditions and high – almost quantitative – yield;
• reducing agent (in case of 99mTc and kits)
• buffers
• filling materials
• Freeze-drying should be optimized to ensure:
• nice gross appearance
• degradation of components (minimized)
• as low water content as possible, to ensure stability
Criteria for kits to be labelled

Criteria:
• chemical form and medium, applicable for labelling, e.g.
18F- on Kryptofix as nucleophilic, 18F2 as electrophilic agent
123/131I- as iodide, can also be oxidized for electrophilic reactions
99mTcO4-, 188ReO4- generator eluates, to be reduced during labelling
M(III)-chlorides for direct complexation
• pH – depends on the chemical nature of precursor
• non-carrier added or carrier-free state – i.e. high specific activity
• high acivity concentration (given in GBq/ml) – if the labelling
reaction requires
Radiopharmaceutical precursors

• Technetium is a second-row transition metal ([Kr]d5s2).
• Technetium may achieve all oxidation states from -1 to +7
in complexes displaying various coordination geometries.
Technetium Chemistry
Compound Coordination
Oxidation state
and
electronic
configuration  Geometry Coordination
number
+ 7 (d0) [TcH9]2- Trigonal prismatic 9
+ 6 (d1) [TcO4]2- Tetraedron 4
+ 5 (d2) [Tc(diars)2Cl4]+ Dodecaedron 8
+ 4 (d3) [TcCl6]2- Octaedron 6
+ 3 (d4) [TcCl(CDO)3BCH3] Capped Octaedron 7
+ 2 (d5) [Tc(diars)2] Octaedron 6
+ 1 (d6) [Tc(CNC(CH3)3)6]+ Octaedron 6
+ 0 (d7) [Tc2(CO)10] Octaedron 6
- 1 (d8) [Tc(CO)5]- Not determined 5

Due to their short half-life, all 99mTc-radiopharmaceuticals are
prepared by the user just before administration to the patient.
The general reaction for the preparation of Tc-labeled
radiopharmaceuticals is:
[99mTcO4]- + reducing agent + L [99mTcLn]
This reaction is performed by using a kit, i.e. a vial(s) containing sterile and
pyrogen-free ingredients able to yield the final product within a short time
(5 to 30 min) and in high radiochemical yield (> 95%)
Radiopharmaceutical Preparation with 99mTc: General

M = Metal
Tridentate: aminophosphines, NS2,………..
Tetradentate: cyclam, N2S2,…………
Type of Ligands

Kit Constraints
 Only chemical reactions that require no more than
one or two steps to obtain the final product can be
used.
 The reaction should be carried out in physiological
solution (0.9% aqueous NaCl) and under strictly
controlled sterile and pyrogen-free conditions.
 All ingredients should be of pharmaceutical quality
and used in amounts well below their toxicity limit.
Chemistry in a Kit

 All solutions should be made with Low-Oxygen-Content (LOC) water
(water is boiled and cooled under nitrogen/argon). All steps are
carried
out in sealed vessels under nitrogen bubbling.
 Tin(II) chloride dehydrate is dissolved in LOC HCl (0.1 to 1.0 M).
Solution are made concentrated in order to use low amount of acid.
 If the molecule to be labelled is able to complex Sn2+, tin(II) chloride
solution is directly added to the molecule dissolved in water. If the
molecule does not complex tin(II), or if it is present at low
concentration, a tin complexing anion is first added (pyrophosphate,
tartrate, gluconate, …).
 Other ingredients can be added to the solution (auxiliary reagents,
stabilizers) and the pH is brought to the optimal value.
 Final solution is dispensed in vials and freeze-dried to obtain a
product with a long shelf-life.
Practical aspects of 99mTc
radiopharmaceuticals: how to make a kit

Quality control of 99mTc-radiopharmaceuticals
The most important quality control for 99mTc-radiopharmaceuticals is the
determination of the radiochemical purity (RCP), which is defined as:
“the fraction of the stated radionuclide
present in the stated chemical form”
Note: Often, the exact chemical form of a technetium-labeled compound
cannot be fully established and, as a consequence, appropriate quality
control methods might not be developed. In these situation, the percentage
of unreduced 99mTc (99mTcO4
-) is measured as well as the percentage of
99mTc not existing in the form of a single-molecule coordination complex
(hydrolyzed 99mTc).

(1) Methods used for RCP assay should be simple and reliable.
(2) Thin Layer Chromatography (TLC) is the most frequently used method
especially for radiopharmaceuticals of unknown chemical structure.
(3) Separation of labelled compound from pertechnetate and hydrolyzed Tc can
be performed by one or two chromatographic steps.
(4) HPLC is the preferred method for well chemically characterised compounds.
before after
Solvent front ~ 8-9 cm
99mTc-radiopharmaceutical
& 99mTcO4
-
Cutting line
Deposit line
(Hydrolized 99mTc)
Solvent front ~ 8-9 cm
99mTcO4
-
Cutting line
Deposit line (99mTc-radio
pharmaceutical & Hydrolized 99mTc)
after

Rf =
Fc (distance from the origin to the center of the spot, cm)
Fs (distance from the origin to the solvent front , cm)
Calculation of migration index Rf
Fc
Fs

Chromatographic
chambers TLC strips
Shielded
syringe
pH
measurement
TLC

Radiochromatograph
origin Solvent front
Distance from the origin (cm)
Radioactivity(cpm)

Calculation of the Radiochemical Purity
(RCP, %)
Distance from origin(cm)
cpm
I (impurity)
R
(radiopharmaceutical)
origin
solvent front
RCP (%) =
R (cpm o Ci)
R+I (cpm o Ci)
x 100

99mTc-MAA
-At least 90% of the MAA particles are between 10-90 μm in size; none are >150 μm
in their longest aspect.These are the legal particle size requirements as listed in the
manufacturers' package inserts and in the current USP.
-100, 000-500, 000 particles
- Even though these appear to be very large numbers, there is a very large margin of
safety since fewer than 1/1,000 capillaries are blocked.
-Lung Shunt, P.Hypertension, Pergnant & Pediatric Not more than 60,000
-½ Dose means ½ number of particles

Ge Reflux
99mTc-sulfur colloid or 99mTc-nanocolloid can be done with
½ mCi dose

Physiological distribution – I
• 99mTc-Re-sulphide coll.: ≥ 80 % in the liver & spleen
 5 % in the lungs
• 99mTc-Sulphur coll.: ≥ 80 % in the liver & spleen
• 99mTc-Tin colloid: ≥ 80 % in the liver & spleen
• 99mTc-Human serum albumin:  15 % in the liver
• 99mTc-Macrosalb (HSA MAA): ≥ 80 % in the lungs
 5 % in the liver & spleen

• 99mTc-Medronate (MDP): ≥ 1.5 % in the femur (rat)
 1 % in the liver
 0.05 % in the blood
• 99mTc-Microspheres: ≥ 80 % in the lungs and
 5 % in the liver & spleen
• 99mTc-Succimer (DMSA): ≥ 40 % in the kidneys
 10 % in the liver
 2 % in the stomach
Physiological distribution – II

Tc-99m Pertechnetate
 +7 Valence state, stable
 Pharmacokinetics
• distributes rapidly in extracellular fluid similar
to iodide
• concentrates in thyroid, choroid plexus,
salivary gland and stomach
– Perchlorate (KClO4) adm to block choroid
plexus
• in thyroid, trapped but not organified
– active transport mechanism
• excreted by kidneys and GI Tract

Distribution

 Critical organ- colon
 Clinical use-
• Thyroid- 8 mCi
• brain, testicular, salivary gland and blood pool
imaging-20 mCi

Tc-99m Sulfur Colloid
 +7 Valence state maintained
 Preparation
• acid mixture of Tc-99m pertechnetate and
sodium thiosulfate and heat to boiling for 10
min. Adjust to neutral pH and add gelatin and
EDTA
 Particle size <0.1um to 2.0 um
• Particle size may affect biodistribution
• Particle size >8 um will result in lung uptake
 RCP- >92% USP

• After IV inj, rapidly cleared by RE cells with
T1/2 of 2-3 min
– blood clearance prolonged in cirrhosis
• Normal distribution,
– 80-90% in Liver, 5-10% Spleen, remainder in
bone marrow
– distribution altered by particle size
 Clinical use
• liver-spleen imaging

LIVER SCAN
PARTICLE SIZE ASSESSMENT

LIVER SCAN

Tc-99m Filtered Sulfur Colloid
 Tc-99m SC filtered through 0.1um or
0.2um filter
• Yields 15% to 40%
 Resultant filtered particles have maximum
size equal to filter used
 Use- Lymphoscintigraphy
• Dose 0.5 to 1.0 mCi in very small volume (0.1
ml)

Tc-99m BONE IMAGING AGENTS
 PYROPHOSPHATE
 ETHYLENEHYDYROXY DIPHOSPHONATE
(EHDP)
 METHYLENE DIPHOSPHONATE
 HYDROXYMETHYLENE DIPHOSPHONATE

Tc-99m BONE IMAGING AGENTS
STRUCTURE

Tc-99m MDP
 PHARMACOKINETICS
• RAPID BLOOD CLEARANCE
• CHEMISORPTION ONTO HYDROXYAPATITE
CRYSTALS ON BONE
• 50-60% ID ON BONE AT 3 HRS PI
• Remaining activity excreted in urine
 FORMULATION
• RC IMP- pertechnetate and Tc-HR
• Ascorbic acid/ascorbates added as anti-oxidant
 Clinical Use- Bone Imaging Agent (20 mCi)

BONE SCAN Tc-99m MDP
PROSTATE CANCER

RADIOCHEMICAL IMPURITY- HR

RADIOCHEMICAL IMPURITY- FREE Tc

Tc-99m Macroaggregated Albumin
(MAA)
 MAA prepared by denaturation of HSA with
heat and pH adjustment.
 Radiolabeling- oxidation-reduction with Sn
 Quality Control (USP)
• RC Purity greater than 90%
• Particle size, 90% size between 10-90 u, no
particle should exceed 150 u
• Biological distribution- 80% in lung, no more than
5% in liver at 5-10 min post-inj

(MAA)
 MAA particles per dose 250k optimum
• 280 billion capillaries
• adjust particles/dose by Tc-99m concentration
• Upon inj, 90% of particles trapped in lung
• Eff Half Life 1.5 hrs, particles clear by enzymatic
hydrolysis, phagocytized by RES
• Urinary clearance- 30-40% ID at 24 hrs

(MAA)
 Special considerations
• MAA suspension, must agitate
• Do not draw blood in syringe prior to injection
– cause aggregation
• Use large gauge needle
– can cause particle breakdown
• Use within 8 hrs after preparation
 Clinical Use- Lung imaging

LUNG SCANS Tc-99m MAA
PARTICLE SIZE ASSESSMENT

2/11/2018
 Radiolabeling- Add weak chelate of Tin (+2), crosses
RBC membrane and attaches to Hb. Excess tin
removed. Tc-99m Pertechnetate added, crosses RBC
membrane, reduced and binds to Hb
 Biological T1/2= 20 hrs
 Methods of Radiolabeling
 In-Vitro
 In-Vivo
 In-Vivtro
Tc-99m RBC

Tc-99m RBC
Labeling Methods
 In-Vitro- RBC removed and incubated with Sn-PYP.
Centrifuged. Tc-99m Pert added to cells incubated,
centrifuged and resuspended in saline.
• Most time consuming procedure
• Results in highest labeling efficiency (>90%)
 In-Vivo- Sn-PYP inj, wait 30 minutes, Tc-99m
Pertech injected
• Easiest method to use
• Results in lowest labeling efficiency (appr 80%)
• Drugs may interfere with labeling
• Impaired renal function will interfere with radiolab

Tc-99m RBC
Labeling Methods
 Modified In-vivo- Inject Sn-PYP, After 30 min,
Remove blood sample and incubate with Tc-
99m Pertech in syringe for 10 min, then reinject
• Radiolabeling between the two (85%)
 Clinical Use- Blood Pool Imaging Agent (20 mCi)

HEART, BLOOD POOL IMAGE
Tc-99m RBC

Tc-99m RBC
ANTERIOR, LAO AND RAO VIEW OF HEART

Iodine Contrast Agent and Tc-99m RBC

Tc-99m UltraTag RBC kit
(Mallinckrodt)
 Reaction vial
• Tin (stannous ion)
 Syringe 1
• Sodium hypochloride
 Syringe 2
• Citric Acid/sodium citrate

Tc-99m UltraTag RBC kit
(Mallinckrodt)
 Add 1-3 ml of blood to reaction vial
• Limit ACD, which will inhibit Sn diffusion into RBC
• Sn diffuses into RBC and attaches to Hb
 Add Syringe 1
• Hypochlorite oxidize extracellular tin
 Add Syringe 2
• Citric acid/sod citrate sequester tin and more
available for oxidation by hypochlorite
 Add Tc-99m pertech (10-100 mCi) and react for
20 minutes

Tc-99m Human Serum Albumin
(HSA)
• Biological T1/2= 60-70 min
• At 1 hr post-inj- 35% ID in Blood
 Not agent of choice for normal blood pool
imaging
 Clinically Utilized
• Patients on chemotherapy
• Patients injected with therapeutic amounts of heparin

Tc-99m IDA Agents
(Iminodiacetic acid)
• After iv inj, IDA agents rapidly extracted by
hepatocytes and excreted into biliary tract within 15-
20 min
• Gallbladder visualized at 20 min with subsequent
excretion in intestine
• 1-5% ID excreted in urine
 Newer agents- (agents of choice) good imaging
in presence of high bilirubin
• Tc-99m disofenin (Hepatolite)
• Tc-99m mebrofenin (Choletec)

Tc-99m IDA Agents
 Newer agents- (agents of choice)
• Tc-99m disofenin (Hepatolite)
• Tc-99m mebrofenin (Choletec)
 Agents of choice
• Good imaging in presence of high bilirubin levels up
to 24 mg/dl

Tc-99m IDA Agents
 Drug Intervention Studies
• Morphine- enhancement of gallbladder filling
• Cholecystokinin or fatty meal- enhance gallbladder
emptying
 Clinical Use- Gall Bladder Imaging Agent (3mCi
to 8 mCi)

Tc-99m IDA Agents
Structure
LIDOCAINE ANALOGS

RENAL IMAGING AGENTS
 Tc-99m DTPA (Pentetate)
 Tc-99m Glucoheptonate (Gluceptate)
 Tc-99m DMSA (Succimer)
 Tc-99m MAG3 (Mertiatide)

Tc-99m Pentetate
• IV inj, rapid distribution thru extracellular spaces,
rapidly cleared from body by glomerular filtration.
– Minimal binding to renal parenchyma
 Clinical Use
• Brain (20mCi) and renal perfusion and renal
clearance rate (5mci-10mCi)

Tc-99m Gluceptate
• IV inj, rapid clearance by kidneys
– At 1 hr- less than 15% ID in blood
• Appr 40% excreted in urine within 1 hr
– up to 15% retained in kidney
• Renal retention greater in cortex than medulla
– renal excretion due to glom filtration and tubular
secretion
 Clinical Use
• dynamic and static renal images, brain imaging
• renal morphology- radiation dose to kidneys significantly
less than DMSA

Tc-99m DMSA (Succimer)
• Cleared from plasma with T1/2 of 60 min
• 50% accumulates in renal cortex, 16% excreted in urine
at 2 hrs
 Clinical Use
• Evaluation of renal parenchyma (5 mCi)
– radiation dose to kidneys higher than Gluceptate
 Rph Prep
• must be used within 6 hours after prep
– due to instability and photosensitivity
• Change in oxidation state (alkaline) results in different
biodistribution

Tc-99m DMSA (Succimer)
 Rph Prep
• must be used within 6 hours after prep
– due to instability and photosensitivity
• Change in oxidation state from +3 (acid) to +5 (alkaline)
results in different biodistribution
– From renal cortical imaging to medullary thyroid
cancer imaging

Tc-99m MAG3 (Mertiatide)
• Excreted from kidneys by tubular secretion and glom filtr
 Replaces I-131& I-123 Hippuran
 Clinical Use
• Assessment of renal function (8mCi)
 Rph QC
• package insert requires SepPak (ion exchange chrom)
• Required RC purity must be greater than 95%
 Rph Form- Boiling, Eluate within 6 hrs post elution
new kit using puffer without boiling

Tc-99m MAG3 (Mertiatide)
 Rph Formulation
• After Tc addition, boiling for 10 minutes
• Transchelation reaction
• Use within 6 hrs post preparation
 Photosensitive

MAG3 Structure

CARDIAC IMAGING AGENTS
 Tc-99m Sestamibi (Cardiolite)
 Tc-99m Tetrofosmin (Myoview)
 Tc-99m Teboroxime (Cardiotec)

Tc-99m SESTAMIBI
 DISTRIBUTION AND KINETICS
 FORMULATION AND QC
 CLINICAL INDICATIONS AND USE

Tc-99m SESTAMIBI
KINETICS AND BIODIST
 LIPOPHILIC MONOVALENT CATION COMPLEX
• SEQUESTERED WITHIN CYTOPLASM AND
MITOCHONDRIA
 60-65% OF ACTIVITY EXTRACTED WITH EACH CORONARY
PASS
• 1-1.5% ID IN MYOCARD., BIOL T1/2 CLEAR=6 HRS
• NO REDISTRIBUTION, TIME OF IMAGING NOT CRITICAL
• RAPID BLOOD CLEARANCE, 8% ID AT 5 MIN POST INJ
 MAJOR CLEARANCE THRU HEPATOBILIARY SYSTEM
• AT 48 HRS, 27% ID EXCRETED IN URINE, 33% ID
CLEARED THRU FECES

Tc-99m SESTAMIBI
HUMAN BIODISTRIBUTION AT 60 MIN
(%ID, MEAN  SD)
ORGAN
HEART
LUNG
LIVER
GALLBLADDER
KIDNEY
THYROID
LEGS (MUSCLE)
BLADDER
SPLEEN
REST
1.0 ± 0.4
0.9 ± 0.5
5.6 ± 1.6
3.5 ± 2.5
6.7 ± 0.7
0.2 ± 0.06
11.1 ± 1.0
8.7 ± 4.2
1.0 ± 0.9
EXERCISE
1.4 ± 0.3
1.4 ± 1.2
2.4 ± 1.6
2.5 ± 1.5
6.7 ± 3.9
0.2 ± 0.2
22.2 ± 5.7
6.3 ± 0.7
0.4 ± 0.3

MYOCARDIAL PERFUSION IMAGING
Tc-99m SESTAMIBI
REST, AT 5, 30, 60 AND 180 MIN

Tc-99m SESTAMIBI
STRESS, AT 5, 30, 60 AND 180 MIN

Tc-99m SESTAMIBI
PHARMACEUTICAL PREPARATION
 ADD PERTECH TO KIT (25-1500 mCi, 1-3 ML)
• REMOVE EQUAL VOLUME OF HEADSPACE
 PLACE UPRIGHT IN BOILING WATER FOR 10
MIN
 REMOVE AND COOL FOR 15 MIN
 PERFORM QC PROCEDURE
• RC PURITY SHOULD BE GREATER THAN 90%
 USUAL DOSE 10-30 mCi
 USE WITHIN 6 HRS AFTER FORMULATION

Tc-99m SESTAMIBI
INDICATIONS AND USE
 DIAGNOSIS AND LOCALIZATION OF
MYOCARDIAL INFARCTION
 USEFUL IN DISTINGUISHING NORMAL FROM
ABNORMAL MYOCARDIUM
 EVALUATING MYOCARDIAL FUNCTION
USING FIRST-PASS TECHNIQUE

CARDIAC TOMOGRAPHY
Tc-99m SESTAMIBI

Tc-99m TETROFOSMIN
(MYOVIEW)
 DISTRIBUTION AND KINETICS
 FOMULATION AND QC
 CLINICAL INDICATIONS AND USE

Tc-99m TETROFOSMIN
DISTRIBUTION AND KINETICS
 RAPID MYOCARDIAL UPTAKE
 MYOCARDIAL ACCUM PROPORTIONATE TO REGIONAL
BLOOD FLOW
 MYOCARD UPTAKE (1-1.5%) ALLOWS IMAGING 5 MIN-4
HR POST INJ
 BINDS WITHIN MYOCYTE, NO SIGNIFICANT
REDISTRIBUTION
 RAPID CLEARANCE FROM BLOOD, LUNG AND LIVER
 APPR 40% EXCRETED VIA URINE AND 26% VIA FECES

TETROFOSMIN KIT
 EACH 10-ML GLASS VIAL CONTAINS A
MIXTURE OF
• 0.23 mg TETROFOSMIN
• 0.32 mg DISODIUM SULPHOSALICYLATE
• 0.03 mg STANNOUS CHLORIDE
DIHYDRATE
• 1.0 mg SODIUM D-GLUCONATE
• 1.6 mg SODIUM HYDROGEN CARBONATE

Tc-99m TETROFOSMIN PREPARATION
 RECONSTITUTE VIAL WITH 4-8 ML Tc-99m
PERTECHNETATE
 RADIOACT CONCEN OF PERTECH CANNOT
EXCEED 30mCi/ML
 GENTLY SHAKE VIAL AND ALLOW TO STAND
AT RM TEMP FOR 15 MIN
 STORE RECONSTITUTED SOLN AT RM TEMP

Tc-99m TETROFOSMIN
INDICATIONS AND USE
 DIAGNOSIS AND LOCALIZATION OF
MYOCARDIAL INFARCTION
 USEFUL IN DISTINGUISHING NORMAL FROM
ABNORMAL MYOCARDIUM
 EVALUATING MYOCARDIAL FUNCTION
USING FIRST-PASS TECHNIQUE

Tc-99m TEBOROXIME
(CARDIOTEC)
 Neutral Lipophilic Complex
 Radiolabeling using a Template Synthesis
 Myocardial Extraction- very high
• 3% ID in heart
• Rapid Myocardial Washout- within 15 min
• Imaging must be performed within short time
after injection
 Major route of excretion- hepatobiliary

BRAIN PERFUSION IMAGING AGENTS
 Tc-99m Exametazime (Ceretec)
 Tc-99m Bicisate (Neurolite)

Tc-99m Exametazime
 Lipophillic compound that crosses BBB
 Exists 2 stereoisomers
• d,l Form- much higher brain uptake
• meso form
 Rph preparation and QC
• Tc-99m Pertech must be <2 hr old. Generator must have
been eluted within 24 hrs
• RC purity must be >80% as lipophillic component
• If not stabilized, must be used within 30 min after prep
• Stabilized with methylene blue, must be used within 4 hrs

Tc-99m Exametazime
• Lipophillic Rph crosses BBB and is metabolized
intracellularly to polar species which is trapped
• 3.5-7% ID in brain within one minute after injection
• Washout from brain approx 15%
 For leukocyte labeling
• Methylene Blue cannot be added to prep
• Rph is selectively taken up by neutrophils

Tc-99m Exametazime
4 hr Anterior Images
MIXED MESO D,L

Tc-99m Exametazime
1 Hr Images
MIXED MESO D,L

Tc-99m Neurolite
 Lipophillic Rph
• mechanism of uptake the same
 Rph Formulation easier
 More stable Rph

Practical Aspect of Tc 99m radiopharmaceuticals

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Practical Aspect of Tc 99m radiopharmaceuticals