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PET Radiochemistry and PET Radiopharmaceuticals312
by an electric pump, whereby various components pass out of the column at different rates
depending on their molecular weights. The fractions are collected at different times. The different
components can then be identified and quantitated either by counting the radioactivity in each
fraction with a counter, or by measuring their absorbance with an ultraviolet (UV) monitor.
Another common method of determining the radiochemical purity is the thin layer
chromatography (TLC). In this method, a drop of the radiopharmaceutical sample is spotted on a
solid phase paper strip (e.g., silica gel, Whatman) and then the paper is placed vertically in a jar
containing a small amount of an appropriate solvent, taking care that the spotted area remains
above the solvent. The solvent flows along the paper strip, and different components of the
sample will flow at different rates along the strip depending on their solubility in the solvent.
The ratio of the distance traveled by a component to the distance traveled by the solvent front is
called the Rf value. When the solvent front reaches the top of the strip, the strip is removed and
scanned for the distribution of components along the strip. Alternatively, the strip is cut into
several segments (e.g., 10 segments), and the activity in each segment is measured by a counter.
From the counts of the segments, the radiochemical purity can be calculated.
Biological Tests
Biological tests include sterility testing, pyrogen testing, and toxicity testing.
Sterility: Sterility indicates the absence of any viable bacteria or microorganisms in a
radiopharmaceutical preparation. All radiopharmaceuticals must be sterile prior to administration
to humans, and it is normally accomplished by filtering the product through a 0.22µm membrane
filter, or heating the sample to 120ºC for 20 minutes at a pressure of 18 pounds per square inch.
The PET radiopharmaceuticals are normally sterilized by filtration because of their short halflife. However, molecules like 18F-FDG, which can withstand high temperatures, can be sterilized
by rapidly autoclaving at 134ºC for 4 minutes.
Sterility tests are normally performed by incubating the sample with fluid thioglycollate
medium at 30º to 35ºC for 14 days or with soybean-casein digest medium at 20º to 25ºC for 14
days. The sample volume should be as large as that for human dosage. If bacterial growth is
observed in either test, the preparation is considered asterile. For PET radiopharmaceuticals,
these tests are performed “after the fact” because of their short half-life.
Pyrogenicity: Pyrogens are polysaccharides or proteins produced by the metabolism of
microorganisms, and upon administration, cause undue symptoms such as fever, flushing, chill,
sweating, malaise, etc. These symptoms typically set in 30 minutes to 2 hours after administration
and are rarely fatal. There are no specific methods of making a preparation pyrogen-free, and the
only way to avoid pyrogens is to strictly follow the method of preparation employing meticulous
aseptic technique so that microbes are not introduced into the sample.
Tests for pyrogens include a rabbit test, in which rabbits are administered with the
radiopharmaceutical and their rectal temperatures are monitored. From the rise in temperature in
PET Radiochemistry and PET Radiopharmaceuticals 313
the rabbits, pyrogenicity of a sample is determined. However, a simpler and quicker method is
the so-called limulus amebocyte lysate (LAL) test. In this test, the lysate of amebocytes from the
blood of the horseshoe crab (limulus polyphemus) is mixed with the sample and incubated at
37ºC. An opaque gel is formed within 15 to 60 minutes depending on the concentration of
pyrogens. For PET radiopharmaceuticals, these tests are performed “after the fact”.
Toxicity: The toxicity of a radiopharmaceutical causes alteration in the histology or physiologic
functions of an organ or even death of a species after in vivo administration. It is commonly
characterized by LD50/60, which is defined as the quantity of a sample that kills 50% of the
species within 60 days after administration. It must be established at least in two species before
human administration, and the dosage to the humans is decided by a large safety factor. Toxicity
arises from the pharmaceutical part and most PET radiopharmaceuticals are not toxic for human
administration.
USP Specifications for Routinely prepared and used PET
Radiopharmaceuticals (10)
18
F-fluorodeoxyglucose
Appearance: Clear
pH: 4.5 to 7.5
Specific Activity: Not less than 1 Ci (37 GBq)/µmol.
Radionuclidic Purity: Not less than 99.5 % should correspond to 511 keV,
1.022MeV or Compton scatter peaks of 18F, with no
individual impurity present more than 0.1%.
Chemical Purity: Major impurities are Kryptofix 2.2.2 and 2-chloro 2-
deoxy-D-glucose, which are determined by TLC.
Kryptofix 2.2.2 should not exceed 50g/ml of the sample
volume, and 2-chloro-2-deoxy-D-glucose should not
exceed 1 mg per total volume of the batch produced.
Radiochemical Purity: It is determined by TLC using activated silica gel as the
solid phase and a mixture of acetonitrile and water (95:5)
as the solvent. The Rf value of 18F-FDG is 0.4. The
radiochemical purity should be >90%.
6-18F-L-F1uorodopa
Appearance: Clear
pH: 6 to 7
Specific Activity: Not less than 100mCi (3.7GBq)/nmol
PET Radiochemistry and PET Radiopharmaceuticals314
Radionuclidic Purity: Not less than 99.5% correspond to 511 keV, 1.022 MeV
or Compton scatter peaks of 18F, with no individual
impurity present more than 0.1%.
Chemical Purity: Since the most common method of production utilizes
organo-mercury precursor, mercury is the major toxic
impurity. It is determined by atomic absorption
spectrometry and its USP limit is 0.5pg/ml of L-dopa
solution.
Radiochemical Purity: It is determined by the HPLC method or ion pair
chromatography. The USP limit is 95% of the total
radioactivity in the form of 6-18F-L-fluorodopa.
13
N-Ammonia
Appearance: Clear
pH: 4.5 to 7.5
Specific Activity: no carrier added
Radionuclidic Purity: Not less than 99.5% correspond to 511 keV, 1.022 MeV
or Compton scatter peaks of 18F, with no individual
impurity present more than 0.1%.
Chemical Purity: Aluminum and titanium are the common impurities,
determined by colorimetric methods. The USP limit of
Al3+ is 10µg/mI of the solution.
Radiochemical Purity: It is determined by the HPLC method. The radiochemical
yield should be greater than 95%.
References
1. Hamacher K, Coenen HH, St6cklin G. Efficient stereospecific synthesis of NCA 2-[18Fl-fluoro-2-
deoxy-D-glucose using aminopolyether supported nucleophilic substitution. J Nucl Med 1986; 27:
235.
2. Machulla HJ, Blocher A, Kuntzch M, et al. Simplified labeling approach for synthesizing 3'-deoxy-
3'-[18F]fluoro-thymidine [18FIFLT. J Radioanal Nucl Chem 2000; 243: 843.
3. Luxen A, Guillaume M, Melega WP, et al. Production of 6-[18F]fluoro-L-dopa and its metabolism
in vivo-a critical review. Nucl Med Biol 1992; 19: 149.
4. Le Bars D, Fluorine-18 and medical imaging: Radiopharmaceuticals for positron emission tomography.
J Flourine Chem 2006; 127: 1488-93.
5. Meyer GJ, Ostercholz A, Handeshagen H. 15O-water constant infusion system for clinical routine
application. J Label Comp Radiopharm 1986; 23: 1209.
6. Welch MJ, Kilbourn MR. A remote system for the routine production of oxygen15
radiopharmaceuticals. J Label Comp Radiopharm 1985; 22: 1193.
PET Radiochemistry and PET Radiopharmaceuticals 315
7. Wieland D, Bida G, Padgett H, et al. In-target production of [13N]ammonia via proton irradiation of
dilute aqueous ethanol and acetic acid mixtures. Appl Radiat Isot 1991; 42: 1095.
8. Mitterhauser M., Wadsak W., Krcala A., et al. New aspects on the preparation of [11C]acetate-a
simple and fast approach via distillation. Appl Radiat Isot 2004; 61: 1147.
9. Mitterhauser M., Wadsak W., Krcala A., et al. New aspects on the preparation of [11C]Methionine-a
simple and fast online approach without preparative HPLC. Appl Radiat Isot 2005; 62: 441.
10. US. Pharmacopeia 26 & National Formulary 21. United States Pharmaceutical Convention, Rockville,
MD; 2003.
Other suggested reading
1. McCarthy TJ, Welch MJ. The state of positron emitting radionuclide production in 1997. Semin Nucl
Med 1998; XXVII: 235.
2. Saha GB, MacIntyre WJ, Go RT. Cyclotrons and positron emission tomography for clinical imaging.
Semin Nucl Med 1992; 22: 150.
3. Saha GB. Fundamentals of Nuclear Pharmacy. 5th ed. New York: SpringerVerlag, 2004.
4. Stocklin G, Pike VW, eds. Radiopharmaceuticals for Positron Emission Tomography. Dordrecht, The
Netherlands: Kluwer Academic, 1993
Combined PET/CT : Technical Aspects
and Image Registration
Habib Zaidi
Despite the fact that the introduction of dedicated dual-modality imaging systems designed
specifically for clinical practice is relatively recent, the potential advantages of combining
anatomical and functional imaging has been recognized for several decades by radiological
scientists and physicians (1). Many of the pioneers of nuclear medicine recognized that a
radionuclide imaging system could be augmented by adding an external radioisotope source to
acquire transmission data for anatomical correlation of the emission image. However, the
conceptual designs were never reduced to practice or implemented in either an experimental or a
clinical setting until Hasegawa and colleagues (University of California, San Francisco) pioneered
in the 1990s the development of dedicated SPECT/CT (2) and later Townsend and co-workers
(University of Pittsburgh) pioneered in 1998 the development of combined PET/CT imaging
systems, which have the capability to record both radionuclide and x-ray data for correlated
functional/structural imaging (3,4). Thereafter, SPECT/CT and PET/CT dual-modality imaging
systems were introduced by the major scanner manufacturers for routine clinical use where
approximately more than 80% of PET systems sold annually are combined PET/CT units.
The anatomical information from PET/CT improves the differentiation of physiological
(normal) uptake of FDG and other radiopharmaceuticals from that associated with disease, and
thereby can reduce false positive errors in comparison to lesion characterization when radionuclide
imaging is used alone. By providing high-resolution anatomical information from CT, dualmodality imaging also correlates functional and anatomical data to improve disease localization
and facilitates treatment planning for radiation oncology or surgery.
Capabilities of dual-modality PET/CT imaging
By providing high-resolution anatomical information from CT, dual-modality imaging
correlates functional and anatomical data to improve disease localization (5-9) and facilitates
treatment planning for radiation oncology or surgery. Dual-modality imaging also can account
consistently for differences in reconstruction diameter, offsets in isocenter, image reconstruction
31 6
Combined PET/CT:Technical aspects and image registration 317
coordinates, and image format (e.g., 512512 vs. 128128) between the CT and radionuclide
image geometries to perform image coregistration and image fusion. Depending on the design of
the system, image registration software also may be needed to account for table sag or for
misalignment when the patient moves between the CT and PET image scans. Generally, the
coordinate systems implicit in the PET and CT image geometries are calibrated with respect to
each other using fiducial markers that are scanned with both CT and PET imaging. The image
registration must be confirmed to avoid misregistration errors in the dual-modality images or in
the PET image reconstructed using CT-derived attenuation maps.
PET/CT has demonstrated its ability to facilitate attenuation correction using a patientspecific attenuation map derived from CT that can be produced faster and more accurately than
attenuation maps generated with external radionuclide sources (10). Some caution is, however,
essential when using contrast agents and in presence of metallic implants, which may lead to
visible artefacts on CT and consequently on CT-based attenuation-corrected PET images (11,12).
Figure 1 presents a flowchart of the major steps involved from data acquisition to fused image
display. Firstly, the CT processor corrects and reconstructs the CT data. This is followed by
down sampling (voxel match) of the resulting CT images to PET image resolution and energy
scaling from CT to PET energies using one of the available techniques (bilinear calibration curve
or hybrid methods) (10). The derived attenuation map is then forward projected to generate the
attenuation correction factors (ACFs) required to correct the PET data for photon attenuation.
The PET processor reconstructs the attenuation corrected emission sinograms, which are finally
overlaid on the CT images and displayed on a shared console.
Display fused
Display fused
Display fused
PET/CT images
PET/CT images
PET/CT images
Attenuation corrected
Attenuation corrected
sinograms
sinograms
ACFs
ACFs
x
xx
Reconstruct
Reconstruct
Reconstruct
PET images
PET images
PET images
Forward project
Forward project
Attenuation
Attenuation
map
map
CT
CTCT
sinograms
sinograms
Transmission
Transmission
Reconstruct
Reconstruct
CT images
CT images
CT image
CT image
Move patient table
Move patient table
Downsampling
Downsampling
PET
PETPET
Emission
Emission
sinograms
sinograms
Pre-correct
Pre-correct
Energy scaling Resolution match
Energy scaling Resolution match
Figure1: Flowchart of a typical PET/CT data acquisition protocol illustrating the major steps
involved for generating attenuation correction factors required for CT-based attenuation correction
in PET.
The anatomical and functional information from a PET/CT imaging system are complementary
in that together they provide information that cannot be easily discerned from one type of image
alone (13). This is best illustrated in oncologic applications where anatomical imaging often is
needed to differentiate whether the radiopharmaceutical has localized in response to disease (e.g.
in the primary tumour, lymphatic system, or metastatic site) (5,6,8,14,15) or as part of a benign
process (e.g. in the GI tract, urinary system, or in response to inflammation) (4). Moreover, the
Combined PET/CT:Technical aspects and image registration318
process of differentiating normal from abnormal uptake of 18F-FDG can be complicated by the
relative paucity of anatomical cues in the 18F-FDG scan, making it necessary for the diagnostician
to refer to anatomical images obtained from CT or MRI to correlate the structural and functional
information needed to complete the analysis.
Design features of PET/CT units
The first combined PET/CT system was developed by Townsend and co-workers at the
University of Pittsburgh in 1998 (3,16,17). The system was configured by combining a Somatom
AR.SP spiral CT scanner (Siemens Medical Systems) in tandem with the PET detectors from an
ECAT ART PET system (CTI/Siemens). The PET subsystem consisted of two arrays of bismuth
germanate (BGO) block detectors covering 16.2 cm in the axial direction with 24 partial detector
rings operated without septa, allowing the PET data to be acquired in a fully 3-dimensional
mode. The CT scanner was a third generation helical CT scanner that has an x-ray tube operated
at 110-130 kVp with a 6.5 mm Al-equivalent filtration and having a xenon x-ray detector with
512 elements. Both the CT components and the PET detectors are mounted on opposite surfaces
of the rotating stage of the CT system, and during imaging are rotated continuously at a rate of
30 rpm. The system has a common patient table, with the patient translated between the centers
of the CT and PET imaging planes, which were offset axially by 60 cm. On the prototype
system, an axial extent of 100 cm in the patient could be covered by simple table translation
(16,17) with the PET and CT images acquired sequentially rather than simultaneously. The PET/
CT prototype was operational at the university of Pittsburgh from May 1998 to August 2001,
during which over 300 cancer patients were scanned. These pioneering studies by Townsend and
his colleagues demonstrated both the feasibility and the clinical benefit of combined PET/CT
scanning, and prompted significant interest from the major medical imaging equipment
manufacturers who now all have introduced commercial PET/CT scanners for clinical use.
PET/CT scanners now are available from all of the major medical imaging equipment
manufacturers (GE Healthcare Technologies, Siemens Medical Solutions, and Philips Medical
Systems) (4). Current systems have up to 64 slice CT capability and have radionuclide detectors
with either 2D or 3D PET imaging capability. The PET scanner can have either bismuth germinate
(BGO), lutetium oxyorthosilicate (LSO), or gadolinium oxyorthosilicate (GSO) scintillators. The
CT study typically is used for both localization of the FDG uptake (5,7,8) as well as for
attenuation correction of the PET image. In addition, the use of CT in comparison to external
transmission rod sources for producing the attenuation data increases patient throughput by
approximately 30% (18). As noted above, the PET/CT system also has a specially designed
patient table that is designed to minimize deflection when it is extended into the patient port.
The integration of the PET and x-ray CT imaging chains in a dual-modality imaging system
requires special considerations beyond those needed for scanners designed for single modality
imaging alone. One challenge is offered by the presence of x-ray scatter from the patient that has
the potential to reach and possibly damage the PET detectors, which are designed for the
relatively low photon fluence rate encountered in PET imaging (4,17,19). To avoid this possibility,
the PET detector in a PET/CT system typically is offset in the axial direction from the plane of
the x-ray source and detector.
Combined PET/CT:Technical aspects and image registration 319
As noted above, all dual-modality systems rely on separate x-ray and radionuclide imaging
chains that must be supported on a common mechanical gantry to maintain consistent spatial
relationship between the two data sets, and allow the detectors to be rotated and positioned
accurately for tomographic imaging. The requirements for translational and angular positioning
accuracy are, of course, different for CT and PET. For example, CT requires approximately 1000
angular samples acquired with an angular position and centre of rotation maintained with
submillimeter accuracy. In comparison, PET has a spatial resolution of a few millimetres, and
therefore can be performed with an accuracy of slightly less than a millimeter for clinical
imaging.
The mechanical gantry of the PET/CT system obviously must be designed to satisfy the
requirements for both the PET image and for CT. In comparison to SPECT/CT in which the
gamma camera is rotated around the patient during data acquisition, PET typically (but not
always) is performed using a dedicated high-end stationary detector ring. A PET/CT system
therefore can be configured by designing a gantry that mounts a stationary PET detector ring in
tandem with a platform that rotates the CT imaging chain around the patient using a mechanical
configuration similar to that used in a conventional diagnostic CT scanner. Alternatively, a
partial ring of PET detectors can be rotated to acquire the PET data using the same rotating
platform as the CT subsystem. This approach was taken by Townsend and his colleagues in their
implementation of the first PET/CT system (3,20,21), and is an alternative for a more economical
dual-modality system in comparison to those that use a full-ring of PET detectors. All of these
mechanical designs have been used in commercial dual-modality systems and obviously offer
trade-offs in terms of their performance and cost.
The patient table is another seemingly simple, yet important element of a dual-modality
scanner (4,17). Most imaging systems use cantilevered patient tables to support the patient in the
bore of the imaging system. Patient tables are designed to support patients weighing up to 500
pounds, but obviously deflect to varying degrees when they are loaded and extended with normal
adult patients. However, dual-modality systems use x-ray and PET imaging chains in tandem and
thereby require longer patient tables than conventional imaging systems. Moreover, the table
extension and the degree of deflection can be different for the x-ray and PET imaging chains,
which can introduce a patient-dependent inaccuracy in the registration of the x-ray and radionuclide
images. This problem is overcome by several different methods. The first uses a patient table,
which is supported in front of the scanner, with a secondary support between or at the far end of
the x-ray and radionuclide imaging chains to minimize table deflection. A second approach
adopted by Siemens Medical Solutions uses a patient table that can be fixed on a base that is
translated across the floor to extend the patient into the scanner. Since the patient platform is
stationary relative to its support structure (which acts as a fulcrum), the deflection of the patient
table is identical when the patient is positioned in the radionuclide imager or the CT scanner.
Finally, in modern PET/CT scanners, the computer systems are well integrated in terms of
system control, data acquisition, image reconstruction, image display, and data processing and
analysis (17,22). The dual-modality system must calibrate the CT data so that it can be used as
an attenuation map to correct the radionuclide data for photon attenuation (23-27). For physician
review, the PET/CT system also typically registers the CT and radionuclide data and presents the
Combined PET/CT:Technical aspects and image registration320
radionuclide image as a colour overlay on the grey-scale CT image. Finally, software tools are
provided that, for example, allow a cursor placed on the CT image by the operator with another
cursor automatically placed in the identical position on the radionuclide image, and vice versa.
These software functions allow the operator to utilize the dual-modality data in correcting,
viewing, and interpreting and obviously are important design elements in modern dual-modality
imaging systems.
Challenges and future of dual-modality imaging
Traditionally, CT data were acquired following a breath-hold, whereas PET data were acquired
over several minutes with the patient breathing quietly (Figure 2). However, these breathing
protocols can lead to misregistration artefacts due to anatomical displacements of the diaphragm
and chest wall during a PET/CT scan (1). For example, if the position of the diaphragm is
displaced in the CT scan, which then is used as an attenuation map for the radionuclide data, this
displacement can lead to an underestimate or overestimate of radionuclide uptake in the
reconstructed emission data. The discrepancy in diaphragmatic position between PET and CT
can result in the appearance of the so-called “cold” artefact at the lung base. A recent study (28)
noted that in 300 patients with proven liver lesions; approximately 2% appeared to have the
lesion localized in the lung due to respiratory motion. Care therefore must be taken when
interpreting results from patients with disease in periphery of the lung where noticeable
radiopharmaceutical uptake may be contributed by respiratory-induced motion artefacts rather
than disease (1). Likewise, patient motion also occurs due to cardiac motion, peristalsis, and
bladder filling, all of which can lead to motion blurring or misregistration errors between the
PET and CT image acquisitions. Figure 3 illustrates typical misregistration between PET and CT
scan of the patient because of cardiac motion as the external body surfaces are perfectly registered.
Modern dual-modality scanners now use CT technology that can acquire the anatomical data
within a few seconds after the patient is positioned on the bed. For this reason, the CT acquisition
Figure2: An example of typical image registration problems related to thoracic CT and wholebody 18F-FDG PET showing better registration when both scans are acquired with similar breathing
patterns (bottom) whereas the diagnostic quality breath-hold CT scan (top) shows better lung
definition.
Combined PET/CT:Technical aspects and image registration 321
rarely is the factor that limits the speed of the dual-modality image acquisition in comparison to
SPECT or PET that can consume several minutes to complete. If additional increases in scan
speed are needed, these must be implemented using faster radionuclide scans using newer detector
technologies, faster scintillators, increased computing power, and more efficient scanner
architectures or detector designs than are currently being used. In PET, this includes the possibility
of replacing conventional PET block detectors with LSO panel detectors (4,29) which would
cover a larger axial extent of the patient (with the goal of achieving 5 min scan times) allowing
much faster scan times than are achievable with current systems. Regardless, faster scan speeds
both improve patient comfort and limit the time during which patient motion can occur during
the study. In addition, faster scan speeds can promote faster patient throughput and thereby
increase system utilization and cost-effectiveness of the study.
Similarly, it is expected that the technology of small animal SPECT/CT (30) and PET/CT
(31) will continue to advance. Current small animal radionuclide SPECT systems obtain
submillimeter spatial resolution at the cost of reduced detection efficiency. Newer multi-pinhole
SPECT systems are under development and offer both improved geometric efficiency and spatial
resolution in comparison to current radionuclide imaging approaches in a way that would improve
image quality and reduce scan times for dynamic or ECG-gated cardiovascular imaging in small
animals (32,33). Excellent microCT images of live animals are being obtained using cone-beam
x-ray CT imaging and reconstruction (34). The development of microCT systems that allow
cardiac gating and in vivo coronary imaging would be very useful for functional/structural
imaging and quantitative radionuclide assessments of small animals, similar to those that are
expected to be developed for clinical dual-modality imaging. Finally, advances in computing
power will enable the development and implementation of new anatomically-guided statistical
reconstruction algorithms and data processing techniques that will offer advantages for both
clinical and small animal imaging with dual-modality imaging.
Figure3: An example of typical image registration problems related to cardiac motion as the
external body surfaces of the PET and CT images are perfectly registered.
While all clinical and commercial dual-modality systems have been configured in the form
of SPECT/CT or PET/CT scanners, several investigators proposed and in some cases have
implemented and tested prototype dual-modality systems that combine MRI with small-animal
PET (35-38). There are, however, several important challenges that must be overcome in
implementing and operating a combined PET/MRI or SPECT/MRI imaging system. In comparison
to x-ray CT, MRI typically is more expensive, involves longer scan times, and produces anatomical
images from which it is more difficult to derive attenuation maps for photon correction of the
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