**Clinical Pharmacology and Biopharmaceutics Review**

**NDA:**

**Drug Name:** Fludeoxyglucose F 18 Injection

**Study Type:** Clinical Diagnostic Imaging

**Title:** *Literature Review of Fludeoxyglucose F 18 Injection
(\[^18^F\]FDG) pharmacokinetic studies using Positron Emission
Tomography (PET) in different indications.*

**Purpose:** *To provide a critical analysis and summary of known
published articles that can be* *cited to support either a NDA or an IND
submission of this drug product.*

Primary Reviewer: Alfredo R. Sancho, Ph.D.

**SYNOPSIS**

In the past Positron Emission Tomography (PET) radiopharmaceutical have
been evaluated and approved by the Agency for use as radiopharmaceutical
diagnostic agents. PET radiopharmaceutical have a short physical half
life; therefore, they have to be manufactured in a cyclotron near the
site of use, usually hospitals, clinics or academic research institutes.
On November 21, 1997, the President signed the Food and Drug
Administration Modernization Act (FDAMA) into law. Since then, the
Agency has been actively working with the PET community to develop
improved criteria and procedures to evaluate PET products for safety and
efficacy.

Within the various PET radiopharmaceutical available,
^18^F-fluoro-2-deoxyglucose (\[^18^F\]FDG) has been used since the early
1980\'s for oncology and cardiology diagnostic imaging purposes.
\[^18^F\]FDG was approved in 1994 for the measurement of regional
glucose metabolism in human brain to assist in the diagnosis of seizures
and other Central Nervous System (CNS) disorders. The approved
\[^18^F\]FDG dose for this indication was 185 to 370 MBq.

In essence, \[^18^F\]FDG allows the measurement of *in-vivo* glucose
metabolism. Under steady state conditions, cells in a competition with
glucose take up \[^18^F\]FDG. In malignant cells, accelerated aerobic
process and decreased ability to make energy aerobically promote rapid
uptake of glucose and its analogs, ie.\[^18^F\]FDG. Uptake of
\[^18^F\]FDG and glucose is facilitated by the expression of glucose
transport molecules, GLUT1 through GLUT5. Once inside the
cell,\[^18^F\]FDG is phosphorylated, producing a polar entity that can
not diffuse out of the cell. This by­product can be de-phosphorylated
back to \[^18^F\]FDG by glucose-6-phosphatase. This latter process
occurs at a very slow rate. The amount of \[^18^F\]FDG that accumulates
in the cell over a predetermined time can by used to estimate the
glucose uptake rate for that tissue. This estimation can then be used
for differential diagnosis between tissues, e.g. malignant vs. benign
tumors, or viable vs. dead cardiac tissue.

This is a review based on published peer-reviewed scientific literature
articles provided through the Agency. The initial search criteria
included studies published and written in English from January 1990 to
December 1998, regarding safety, efficacy, pharmacokinetics,
pharmacodynamics, and dosimetry for \[^18^F\]FDG in human clinical
trials. The totality of these articles is considered equivalent to the
information provided with a NDA submission. This review will attempt to
follow the same format of a regular review document.

**OBJECTIVES**

-   To assess the pharmacokinetic information present in the published
    literature, as a function of quality, robustness, reproducibility,
    and scientific importance.

-   To recommend pharmacokinetic information and references from the
    reviewed literature, that can be cited by sponsors in their future
    NDA/IND submissions.

-   To recommend pharmacokinetic information and studies that are needed
    to complement the information from the reviewed literature.

Fludeoxyglucose F 18 Injection (2-deoxy-2-\[^18^F\]fluoro-D-glucose) is
an injectable intravenous imaging radiopharmaceutical product for
Positron Emission Tomography (PET). This drug product has been used to
measure deoxyglucose metabolism in a variety of tissues, e.g the
brain.^i,ii^ Fludeoxyglucose F 18 Injection is abbreviated as
\[^18^F\]FDG. The structural formula for \[^18^F\]FDG is the following:

![](media/image2.wmf){width="2.4652777777777777in"
height="1.4909722222222221in"}

\[^18^F\]FDG is a radiolabeled analog of glucose that rapidly
distributes throughout fluids of the entire body after an intravenous
administration. Optimal visual and contrast quality for imaging times
and sequences vary with dose, equipment, region-of-interest (ROI), but
it ranges from 30-60 minutes post-administration and after its initial
clearance phase. This drug product is not extensively involved in
glucose metabolism; it is cleared from most tissues within 24 hours, and
can be eliminated from the body unchanged in the urine.

**TECHNICAL BACKGROUND**

A \"typical\" 1-ml of \[^18^F\]FDG contains 6.8-35.7 mCi (251-1321 MBq)
of 2-deoxy-2­(^18^F\]fluoro-D-glucose and 9-ml of sodium chloride. This
drug product can be produced in various ways, including an automated
radiochemical synthesis unit from a cyclotron produced Fluorine-F^18^.
Fluorine-F^18^ is produced by proton bombardment (in a cyclotron) of
enriched \[^15^O\]water and is bound to
1,3,4,6-tetra-0-acetyl-2-0-trifluoromethanesulfonyl-*β*,
6-D-mannopyranose (mannose triflate) under stereo specific S~N~2
reaction conditions. This renders no carrier added Fludeoxyglucose F 18
Injection. The pH can be adjusted by passage through an ion retardation
resin.

Cyclotrons accelerate subatomic particles (e.g. protons or deuterons)
that interact with stable elements in the targetry system to produce
radionuclides. The main radionuclides produced by a cyclotron for PET
studies are \[^15^0\] oxygen, \[^13^N\]nitrogen, \[^11^C\]carbon, and
(^18^F\]fluorine. These radionuclides have physical half-life of 2
minutes, 10 minutes, 20 minutes, and 110 minutes, respectively. These
radionuclides are then \"converted\" or used to radiolabel compounds
(radiopharmaceutical) that are of physiological interest and can be
administered to patients or animals in a wide range of studies,
including clinical and preclinical studies. Once these
radiopharmaceutical are produced, they need to be utilized promptly, due
to the short half-life of the radionuclides. Hence, there is a need for
automated synthesis systems and a need for placing a properly shielded
cyclotron near the center or hospitals where the studies are to be
conducted.

Fluorine-F^18^ decays by positron (*β*+) emission (249.8 keV, 96.73% per
disintegration) and has a physical half-life of 109.8 minutes. There is
another emission, gamma photons, useful for diagnostic imaging at the
511 keV, resulting from the interaction of the emitted positron with an
electron or positron annihilation. The specific gamma ray constant for
Fluorine-F^18^ is 6.0 R/hr/mCi (0.3 Gy/hr/kBq) at 1-cm. The half-value
layer (HVL) for the 511 keV photons is 4.1 ­mm lead (Pb). The range of
values for the attenuation of radiation are known, an example of it
would be an 8.3 mm thickness of Pb, with a coefficient of attenuation of
0.25, will decrease the external radiation by 75%.

In the last 10 years, there have been rapid advances in radiochemistry
automation production of \[^18^F\]FDG and overall cyclotron technology.
Imaging equipment for PET studies have also had marked improvements. The
initial positron tomograph had a resolution (full width at half maximum)
of 1.5-20 cm and produced only a single transaxial cross sectional
image. Presently, available equipment has a resolution around 5 mm in
all directions and simultaneously produce 15-45 contiguous slices over
an axial span of 10-15 cm, What in the early equipment could not be
accomplished has now become the norm, e.g. whole body acquisitions.
Moreover, organs can be imaged in their entirety with equal resolution
in all dimensions without moving the patient. More importantly, the
obtained data can be reformatted to generate images at any angle through
the organ. Another improvement has been the use of a semi-quantitative
measurement or Standardized Uptake Value (SUV). This is a ratio of
measured radioactivity concentration in a determined lesion or Region of
Interest (ROI) against neighboring normal tissue, to estimate of the
drug product concentration in the ROI. Finally, correction for varying
serum glucose levels and \[^18^F\]­FDG found in the interstitial volume
is been explored.

**BIOLOGICAL BACKGROUND**

Glucose consumption is different in each of the organs within the body;
it further varies with the state of health of each organ. Some organs
will not only consume glucose but also produce glucose or consume it
only under certain specific metabolic or physiological conditions. At a
local regional sub-organ level, these differences in glucose consumption
are evident as well, for within the same organ different regions may
have varying states of health, which directly affect the glucose
consumption, e.g. ischemic heart.

There are three different kinetic steady-state glucose metabolism
models. The first model, which describes the net rate of native glucose
transfer into tissue, is based on the arterio­venous differences and the
plasma flow, using the *Fick* perfusion principle:

***R = FC~a~ - FC~v~ = KC~a~***

in which ***R*** is the net rate of glucose uptake, ***F*** is the
plasma flow, and ***K*** is the net clearance of glucose into tissue at
steady state. The second model, which describes the steady state, is
based on glucose consumption:

***R = k~app~M~e~***

where ***k~app~*** is the net steady-state rate of glucose
phosphorylation and ***M~e~*** is the tissue glucose content. The net
steady-state rate of phosphorylation is the product of the
unidirectional rate of phosphorylation and the isomerization fraction of
glucose to fructose-6-phosphate. The third model of glucose consumption
at steady-state is based on the differences between the arterial
concentration (***C~a~***) and the interstitial concentration of glucose
(***C~e~ =*** ***M~e~/V~d~***) or,

***R = k~1~C~a~ - k~2~M~e~***

where ***k~1~*** is the unidirectional clearance of glucose by the organ
in question.

When a radioactive analog of glucose is administered into the body, the
drug is transported across the endothelial and cellular membranes. It is
then subject to the entire metabolism by enzymes for which it retains
affinity. With the fluorinated glucose analog, fluorodeoxyglucose, the
metabolism includes 1)transport across the blood-tissue barrier and
cellular membranes by the glucose transporter, 2)phosphorylation by
hexokinase, 3)dephosphorylation by glucose-6-phosphatase, but 4)not
isomerization by glucose phosphate isomerase.^iii^ Irreversible
metabolism occurs when glucose-6-phosphates activity is negligible,
e.g.. brain tissue.

Deoxyglucose may have kinetic constants that are different from those of
native glucose, *e.g.* net clearance at steady-state (K). In the brain,
it can be argued that the phosphatase activity is negligible; while in
other organs, phosphatase activity may be too high to ignore.^iv,v^
Therefore it must be determined if the organ-tissue selected and
deoxyglucose model being applied to, has irreversible phosphorylation or
not. Without dephosphorylation, deoxyglucose-6-­phosphate and other
metabolites will accumulate irreversibly within the cell. The
deoxyglucose metabolism model proposed by Sokoloff *et. al.* (1977) has
the net metabolism directly proportional to the quantity in the
precursor pool. The net steady state of uptake is equal to the rate of
phosphorylation multiplied by the apparent steady-state volume of
distribution of unphosphorylated glucose.

Glucose pathway includes the crossing of the endothelium of the
capillaries by facilitated diffusion through cell membranes or
transcellular process, and by bulk flow of water between cells and
paracellular process. The latter process is hindered in some organs due
to high osmotic pressures within the organ, e.g. brain, leading to lower
interstitial glucose concentrations than those found in the circulating
plasma. \[^18^F\]FDG uptake is also accelerated during inflammation
processes, such as in infections, granulomas, abscesses, and other
processes, leading to \"false­ positives\" results and lower specificity.
There is also a great variability in \[^18^F\]FDG uptake between tumor
of different type, location, and size.

**CLINICAL INDICATIONS**

Potentially \[^18^F\]FDG can be used to image any organ-tissue that
utilizes glucose as the main source of energy, assuming that PET
\[^18^F\]FDG images will be used as a differential diagnostic tool.
Nevertheless, there are three main organ-tissues which have been
evaluated in diagnostic \[^18^F\]FDG PET studies. These are brain,
heart, and tumor masses.

**PK/PD BACKGROUND**

It is *[assumed]{.underline}* that \[^18^F\]FDG parallels the
deoxyglucose metabolism in healthy normal human subjects. Hence, the
proposed model in which the arterial blood level is described by a
tri-exponential decay curve. There is consistency in the value for the
early elimination phase (0.2-0.3 minutes) across various studies, while
for the later two phases the numbers vary with no clear indication for a
reason. Samples of the values for the latter two phase of elimination
phases are, 11.6 ±1.l min and 88± 4 min^vi^ or 4.21 ±1.09 and 50.08
4-14.62.^vii^ Within 33 minutes, a mean of 3.9% of the injected dose can
be measured in the urine of normal subjects. Within 2-hours
post-administration, there is a mean of 20.6% of the injected dose found
in the bladder. In most tissues (except the heart)\[^18^F\]FDG is taken
up into the cells and phosphorylated to \[^18^F\]FDG-6-­phosphate at a
rate proportional to the rate of glucose utilization. At this point it
will metabolize to 2-deoxy-2-\[^18^F\]fluoro-6-phospho-D-mannose or
\[^18^F\]FDM-6-phosphate. The phosphorylated deoxyglucose compounds are
then dephosphorylated and the resulting compounds eliminated from the
cells by passive diffusion. Due to the deoxyglucose metabolism
differences between the heart and other tissues mentioned in the
Biological Background section of this review, the heart may require more
than 96 hours to clear the drug product and its metabolites.

**DOSIMETRY**

\[^18^F\]FDG dosimetry published data is available from the
International Commission on Radiological Protection.^viii,ix^ The
following data is the estimated absorbed radiation doses after an
intravenous administration of \[^18^F\]FDG to 70 kg human subject.

![](media/image3.wmf){width="5.324305555555555in"
height="5.218055555555556in"}

The accurate determination of the radiation exposure to critical organs
in patients through dosimetry data is important because it would allow
for dose adjustment to individual patients. Of all the organ-systems
that may be exposed to radiation from the dosing of this product, the
renal system is most affected. Of the various organs of this system, the
bladder is of great concern for it is the organ to receive the highest
dose of radiation.^x^ Actual absorbed doses vary widely depending upon
if the patient is hydrated or not, initial bladder volume, urine output,
voiding schedule, rate of elimination of FDG, residual amount in bladder
after voiding, any renal dysfunction present, and if the patient has a
urinary catheter or not. The method used to calculate the absorbed doses
for the bladder depend also on the MIRD model used, *eg.* a static or
dynamic bladder volume model, and on the method used to generate a
bladder time-activity curve, including decay correction.^xi^ All the
articles reviewed mentioned that decreasing the interval time between
voiding events and/or hydrating the patient to increase the bladder
water volume should reduce the bladder absorbed dose.^xii^

**SAFETY CONCERNS**

The full extent of the effect of fasting, varying blood sugar levels,
and diabetic diseases (e.g. mellitus diabetes) on \[^18^F\]FDG
distribution in humans is not ascertained to date. Diabetic patients may
need stabilization of blood glucose levels on the day before and on the
day of the \[^18^F\]FDG study. Close monitoring should include glucose
blood level, hypotension, hypo- or hyper-glycemia, and arrhythmia.

Other population groups that may need special care would include:

a\) lactating mothers (no studies are available to ascertain if this
drug product or its metabolites are eliminated through breast milk);

b\) pregnant mothers (no studies are available to ascertain if there is
any and to what extent the fetus would be exposed to this drug product);
and,

c\) pediatrics.

No extensive dose range and dose adjustment studies with this drug
product in normal and special populations have been completed. The doses
across adult human studies cited in this review vary from 5 to 10 mCi
(185 to 370 MBq). In children, doses given have been as low as 2.6 mCi.

No overdose effect studies were found within the database of the
literature search completed for this review.

No plasma protein binding in-vivo or in-vitro studies were found within
the database of the literature search completed for this review.

**STUDY REVIEWS**

The initial literature search criteria was to include all studies
related to the pharmacokinetic assessment of \[^18^F\]FDG. This
criterion was later narrowed to studies only after 1991, due to
technological advances and refinements in the PET equipment. The
criteria were again modified to include all studies with no limitations
on dates.

All studies presented in this review were selected based on the
information given in the publication. This information would include the
details of the study protocol/s, the validation and correction methods
used in image and data acquisitions, reproducibility of the results, and
the population number and type used in the studies. Similarities and
differences in \[^18^F\]FDG dose, equipment, data analysis, and image
acquisition protocols were sought among all the publications reviewed.

Four main literature sources can be used for the estimations of absorbed
doses in humans from \[^18^F\]FDG. The amount of activity in the
injected dose of \[^18^F\]FDG measured in a dose calibrator ranged from
74 to 370 MBq. These references are:

1\) International Commission Radiation Protection (ICRP) Publication 53,
Volume l8, No.14,1987.

2\) Estimation of absorbed doses in humans due to IV administration of
\[l8F\]FDG in PET studies. Mejia A, *et. al.* J. Nucl. Med. 32:699-706,
1991.

3\) The Radiation Dosimetry of ^18^F-FDG in Man. Jones, SC., *et. al.*
J. Nucl. Med. 23:613-617, 1982.

4\) Absorbed Dose estimation in PET studies based on the administration
of ^18^F-labelled radiopharmaceuticals. Mejia A.A., *et. al.* J Radiat.
Res. 32:243-261, 1991.

Other publications reviewed do not directly address the need to create
or validate a traditional pharmacokinetic profile for \[^18^F\]FDG,
instead they *\"[assume]{.underline}\"* that this drug product will
follow the *\"[understood]{.underline}\"* fluorodeoxyglucose pathway.
Based on this assumption, \[^18^F\]FDG has been used in a great number
of different clinical indications; mainly because, this drug product is
used to assess glucose metabolism uptake differences between two
adjacent regions of interest (ROI). Notably the following are some
clinical and preclinical publications that can be referenced, depending
on the indication for \[^18^F\]FDG:

1\) Tumor metabolic rates in sarcoma using FDG PET. Eary JF, *et. al.*
J. Nucl. Med. 39:250-­254,1998.

2\) PET in patients with glioma. A predictor of prognosis. Alavi JB,
et.al. Cancer 62:1074­-1078,1988.

3\) Intratumoral distribution of ^18^F-FDG in-vivo: High accumulation in
Macrophages and Granulation tissues studied by microautoradiography.
Kubota R, *et. al* J. Nucl. Med. 33:1972-1980,1992.

4\) Untreated primary lung and breast cancers: Correlation between
^18^F-FDG kinetic rate constants and finding of in-vitro studies.
Torizuka T, *et. al.*

5\) Quantitative ^18^F-FDG PET in pretreatment and grading of Sarcoma.
Eary JF, *et. al.* Clin. Can Res. 4:1215-1220, 1998.

6\) FDG uptake, tumor characteristics and response to therapy: A review.
Smith TAD. Nucl. Med. Comm. 19:97-105,1998.

7\) PET applications in pediatrics. Shulkin BL. Q. J. Nucl Med.
41:281-291,1997.

8\) FDG-PET screening for cerebral metastases in patients with suspected
malignancy. Larcos *G., et. al.* Nucl. Med. Comm. 17:197-198,1996.

9\) Cerebellar glucose consumption in normal and pathologic states using
fluorine-FDG and PET. Kushner M, *et.al.* J. Nucl. Med.
28:1667-1670,1987.

10\) Kinetics of transport and phosphorylation of
2-fluor-2-deoxy-D-gluocse in rat brain. Crane PD *et.al.* J. Neurochem.
40:160-167,1993.

11\) Organ and tumor distribution of ^18^F-FDG in fasting and
non-fasting rats. Paul R, *et. al.* Life Sci. 40:1609-1616,1987.

12\) Reassessment of FDG uptake in tumor cells. High FDG uptake as a
reflection of Oxygen­-independent Glycolysis dominant energy production.
Waki, A, *et. al.* Nucl. Med- Biol. 24;665-670,1997.

13\) Active and Passive mechanisms of ^18^F-FDG uptake by proliferating
and prenecrotic cancer cells in-vivo: A microautoradiography study.
Kubota R, *et. al.* J Nucl. Med. 35-.1067-1075,1994.

14\) Measurements of glucose phosphorylation with FDG and PET are not
reduced by dephosphorylation of FDG-6-phosphate. Kuwabara H, *el. al.*
J. Nucl Med 32:692-698,1991.

15\) Blood-brain transfer of glucose and glucose analogs in newborn
rats. Fuglsang A, *et. al. J.* Neurochem. 46:1417-1428,1986.

**CONCLUSIONS**

The are several key factors used to evaluate these published
peer-reviewed scientific articles, which include:

1\) multiple studies conducted by different investigators where each of
the studies clearly has an adequate design and where the findings across
studies are consistent with each other;

2\) a high level of detail in the published reports, including clear and
adequate descriptions of statistical plans, prospective analytic
methods, study end-points, full accounting of enrolled patients and
their data, and method for calculating all appropriate pharmacokinetic
parameters;

3\) appropriate and clear endpoint determination that can be objectively
assessed by any independent investigator;

4\) robust results that yield a consistent conclusion and does not
require post-hoc analysis; and,

5\) patients enrolled provide the appropriate study strength in relation
to the predetermined objectives.

The sections of the articles evaluated and included in this review were
the Protocol Design, Objectives, Inclusion / Exclusion Criteria, Dose,
Primary Endpoints, Results, Statistical Analysis, and
Pharmacokinetic/Pharmacodynamic Data.

From the data across all the articles included in this review, the
following is the summary of information known or need to be known:

1\. Known information:

> The understanding and knowledge of the behavior of \[^18^F\]FDG is
> based on the known glucose, oxyglucose, and fluoro-D-oxyglucose
> pathways, including the specific enzyme dependent steps.
>
> There is robust background knowledge on \[^18^F\]FDG dosimetry in
> humans and animals.

2\. Need to know information:

> There are no detailed and extensive clinical or preclinical studies to
> validate the assumptions made on the pharmacokinetic profile of
> \[^18^F\]FDG in humans.

The limited pharmacokinetic data available varies between studies with
not clear justification. Hence, the needs to further obtain and evaluate
pharmacokinetic data to recalculate these PK parameters.

There is a need for biodistribution studies in special populations to
assess any metabolic differences and possible dose adjustments,
including elderly, pediatrics, diabetic, hepatic impaired and renal
impaired.

Lacking are human studies that correlate varying doses of \[^18^F\]FDG
with optimal visual quality of acquired images in different
organ-tissues for diagnostic and prognosis purposes.

Alfredo Sancho, Ph.D.

Pharmacologist/Pharmacokinetic Reviewer

Radiopharmaceutical and Imaging Section

Division of Pharmaceutical Evaluation II

Office of Clinical Pharmacology and Biopharmaceutics

*Concurrence:*

David J. Lee, Ph.D.

Team Leader, Pharmacokineticist

Radiopharmaceuticals and Imaging Section

Division of Pharmaceutical Evaluation II

Office of Clinical Pharmacology and Biopharmaceutics

**References**

^i^ Kuwabara H, Evans AC, Gjedde A. *Michaelis-Menten constraints
improved cerebral glucose metabolism* *and regional lumped constant
measurements with \[^18^F\]fluoro-deoxyglucose.* J Cereb Blood Flow
Metab 10:180-189, 1990.

^ii^ Kuwabara H, Gjedde A. *Measurements ofglucose phosphorylation with
FDG and PET are not reduced* *by dephosphrylation of FDG-6-phosphate.* J
Nucl Mcd 32:692-698, 1991.

^iii^ Van Holde, M. Biochemistry. Benjamin Publishing Co., 1990.

^iv^ Crane, PD, Pardfige WM, Braun, LD, Oldendorf WH. *Kinetics of
transport and phosphorylation of 2­fluor-2-deoxy-D-glucose in ral brain.*
J. Neurochem 40:160-167, 1993.

^v^ Fugisang A, Lomholt M, Gjedde A. Blood-brain transfer of glucose and
glucose analogs in newborn rats. J. Neurochem 46:1417-1428, 1986.

^vi^ "Fludeoxyglucose F^18^ Injection \[^18^F\]FDG Diagnostic For
Intravenous Administration\" (1991) The Methodist Medical Center of
Illinois, Peoria, IL 61636

^vii^ Mejia, AA, Nakamura, T, et.al. Absorbed Dose Estimates in Positron
Emission Tomography Studies Based on the Administration of ^18^F-Labeled
Radiopharmaceuticals. 1991 J. Radiat. Res. 32.243-261

^viii^ Jone SC, Alavi A, Christman D, Montañiez 1, Wolf AP, and Reivich
M. *The Radiation Dosimetry of 2-­F-18-fluoro-2-deoxy-D-glucose in man.*
J Nuci Med 23:613-617, 1982.

^ix^ ICRP Publication 53, Volume 18, No. 1-4, 1987.

^x^ Mejia, AA, Nakamura, T, et.al. Absorbed Dose Estimates in Positron
Emission Tomography Studies Based on the Administration of ^18^F-Labeled
Radiopharmaceuticals. 1991 J. Radiat. Res. 32:243-261

^xi^ Dowd, MT, Chen, CT, Wendel, MJ, Faulhaber, PJ, and Cooper, MD.
Radiation Dose to the Bladder Wall from 2-\[^18^F\]
Fluoro-2-deoxy-D-glucose in Adult Humans. 1991 J. Nucl. Med. 32:707-712

^xii^ Jones, SC, Alavi, A, Christman, D, Montañez, 1, Wolf, AP, and
Reivich M. The Radiation Dosimetry of 2-\[F-^18^\]
Fluoro-2-Deoxy-D-Glucose in Man. 1982 J. Nucl. Med. 23:613-617