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REVIEWS AND COMMENTARY

Molecular Imaging: The Vision and
Opportunity for Radiology in the
Future1

䡲 MOLECULAR IMAGING SERIES

John M. Hoffman, MD
Molecular imaging is being hailed as the next great ad-
Sanjiv S. Gambhir, MD, PhD
vance for imaging. This introductory article in the molecu-
lar imaging series to be published over the next several
months in Radiology sets the stage for the subsequent set
of articles by providing relevant definitions and back-
ground information and traces the evolution of molecular
imaging to its current state of research and clinical prac-
tice. It discusses in detail the evolution of molecular imag-
ing and the role that the National Cancer Institute and the
National Institutes of Health have had in the funding and
development of many of the important molecular imaging
research programs that are in existence today. The article
also provides basic information about the complex biology
of the cell and details of the pathogenesis of cancer and
how molecular imaging will be critical for earlier detection
and management of cancer in the future. The article lays
the foundation for the subsequent articles in the series and
describes how and why molecular imaging will be critical
and integral for clinical care of patients in the future. The
introductory article also discusses the relevance of molec-
ular imaging to clinical radiology practice and why it is
critical for the practicing radiologist to understand these
evolving techniques, as they will be the future of imaging.

娀 RSNA, 2007

1
From the Departments of Radiology and Neurology, Uni-
versity of Utah School of Medicine, 2000 Circle of Hope,
Suite 2121, Salt Lake City, UT 84112-5550 (J.M.H.); and
Departments of Radiology and Bioengineering, Molecular
Imaging Program at Stanford, Bio-X Program, Stanford
University, Stanford, Calif (S.S.G.). Received May 2, 2006;
revision requested June 21; revision received October 28;
final version accepted December 11. Address correspon-
dence to J.M.H. (e-mail: john.hoffman@hci.utah.edu).

姝 RSNA, 2007

Radiology: Volume 244: Number 1—July 2007 39

MOLECULAR IMAGING SERIES: Molecular Imaging: Future Vision and Opportunity
T
his is the introduction to a series of
articles on molecular imaging to be
published over the next several
months in Radiology and intended to
show how molecular imaging will be-
come an integral and important part of
clinical radiology practice in the future.
The articles will provide the practicing
radiologist with the necessary back-
ground information to understand the
basic terminology, definitions, and meth-
ods of how molecular imaging is currently
performed and why it will revolutionize
the practice of clinical imaging as we
know it in the not too distant future.
Molecular imaging can be defined as
the in vivo characterization and mea-
surement of biologic processes at the
cellular and molecular level (1,2). A
clinically relevant example is the use of
fluorine 18 [18F]fluoro-2-deoxy-D-glucose
(FDG) positron emission tomography
(PET) and, more recently, that of FDG
PET/computed tomography (CT) in can-
cer diagnosis and management (3,4).
Both of these modalities have shown un-
precedented growth for advancing the
treatment of cancer over the past sev-
eral years (5). The growth is based on
the fact that molecular and metabolic
information are being assessed rather
than only anatomic information. A mo-
lecular or metabolic imaging assessment
provides information that in many in-
stances is of more diagnostic utility than is
simple anatomic information.
The metabolic and molecular infor-
mation provided from PET imaging with
FDG can be considered one of the first
validated and clinically useful tomo-
graphic “molecular imaging” techniques.
More than 70 years ago, Warburg (6)
recognized that malignant tumors have an
increased rate of glycolysis. The initial
rate-limiting enzyme in glucose metabo-
lism in normal tissue and tumors is hexo-
kinase. This particular enzyme is respon-
sible for phosphorylation of glucose to
glucose-6-phosphate and is significantly
overexpressed or upregulated in most
malignancies (7). This is a basic molecu-
lar biologic characteristic of malignant
cells and is thus a molecular signature of
cancer. FDG, which is an analog of deoxy-
glucose, enters cells through the same
pathways of facilitated diffusion as does
40
glucose (via several glucose transporters)
and is subsequently phosphorylated to
FDG-6-phosphate (7). FDG-6-phosphate
is only minimally metabolized and, be-
cause it is negatively charged, remains
metabolically trapped within cells (Fig 1).
FDG PET can therefore be considered as
the imaging of the rate-limiting step of
glucose metabolism, namely hexokinase
activity. The imaging signal detected with
PET tomography is achieved by incorpo-
ration of 18F into FDG, thus enabling de-
tection of the trapped and phosphory-
lated metabolite (8) (Fig 1). FDG PET for
the staging and restaging of malignancy,
metabolic characterization of malignancy,
and monitoring of response to therapy is
an example of a molecular imaging tech-
nique that is used in daily practice (9).
Like any new and evolving scientific
and clinical discipline, such as molecu-
lar imaging, it is important to know its
relevance to the daily practice of medi-
cine. Thus, in this series of articles we
wish to show why the practicing radiol-
ogist will need to understand and appre-
ciate the importance of the following:
(a) the biological information obtained
from molecular imaging studies; (b) ob-
taining additional knowledge or train-
ing, if necessary, in molecular biology,
molecular pharmacology, and genom-
ics; and (c) being knowledgeable and
comfortable with performing diagnostic
molecular imaging studies and inter-
preting images from them on a daily
basis. Furthermore, our goal is to pro-
vide an overview of the current and fu-
ture use of molecular imaging that we
believe will become part of a general radi-
ology practice in the next 5–10 years.
There have been many comprehen-
sive review articles published on molec-
ular imaging (1–4,10–20). These arti-
cles provide the necessary information
to understand the basic molecular biol-
ogy, terminology and definitions (21), and
background relevant to molecular imag-
ing. We do not intend to simply reiterate
this information. Rather, we wish to em-
phasize the potential clinical relevance
and how molecular imaging will be part of
patient care and management in various
areas. We also provide additional infor-
mation on how molecular imaging will be
critically important in the drug discovery
Hoffman and Gambhir
and development process (20,22–26),
with a final article on the issues of regula-
tory approval and reimbursement.
The Evolution of Imaging
During the past 25 years, advancements
and refinements in technology have sub-
stantially broadened the range of avail-
able imaging procedures. Current tech-
niques provide improved resolution and
much clearer and more detailed ana-
tomic images of organs and tissues than
previously possible. CT, ultrasonography
(US), and magnetic resonance (MR) im-
aging provide important structural and
anatomic information. The impact of CT
imaging on the practice of oncology has
been immense. Similarly, the use of MR
imaging in the central nervous system, in
the head and neck region, and for joint
disease has improved the management of
patients. Currently, therapeutic response
criteria are typically based on tumor mea-
surements made from CT scans or MR
images (27). The anatomic information
obtained from a CT scan or MR image
helps in the planning of the surgical ap-
proach and in the definition of the extent
of tumor and assists in the localization of
important normal structures. The use of
contrast agents in both CT and MR imag-
ing has improved diagnostic accuracy.
Despite these substantial improvements
in imaging technology and methods, there
is a need to obtain more relevant molecu-
lar and biochemical information from im-
aging. For example, FDG PET for tumor
staging, cardiac perfusion imaging with
various nuclear medicine and MR imag-
ing techniques, and MR spectroscopy to
characterize brain tumors and prostate
cancer have had a remarkable surge in
use since they provide clinically useful bi-
ologic, biochemical, or physiologic infor-
mation that impacts patient management.
Published online before print
10.1148/radiol.2441060773
Radiology 2007; 244:39 – 47
Abbreviations:
FDG ⫽ [18F]fluoro-2-deoxy-D-glucose
NCI ⫽ National Cancer Institute
Authors stated no financial relationship to disclose.
Radiology: Volume 244: Number 1—July 2007
MOLECULAR IMAGING SERIES: Molecular Imaging: Future Vision and Opportunity Hoffman and Gambhir

The next major area for exploitation substrate such as iodine 131 (131I) or wood, Mo) and 111I– capromab pende-
123
is molecular imaging, where more fun- I is used for determination of a bio- tide (ProstaScint; Cytogen, Princeton,
damental and important molecular, bio- logically relevant abnormality that is im- NJ) imaging for cancer detection.
logic, and biochemical information will aged. Other examples include 123I- and Much of the promise of imaging of
131
be obtained. Molecular imaging will al- I-MIBG, indium 111 (111I) pentetreo- molecular events can be traced to the
low improvement in our ability to char- tide (OctreoScan; Mallinkrodt, Hazel- efforts of the National Cancer Institute
acterize and phenotype diseases on the
basis of biologic and biochemical, in ad-
Figure 1
dition to anatomic, information. In addi-
tion, assessment of the scope of the bio-
logic and biochemical alterations, which
include receptor numbers, pathway reg-
ulation, and signal transduction abnor-
malities, that are present in many dis-
ease entities and analysis of gene, en-
zyme, and protein abnormalities will be
possible. Imaging specialists of the fu-
ture will have at their disposal a set of
technologies with various types of in-
trinsic value in the information they
provide (Fig 2).

Advances in Our Understanding of the

Genetics and Molecular Biology of
Health and Disease
Over the past decade, there has been a
revolution in our basic biologic under-
standing of disease. We have witnessed
the elucidation of the human genome
(28), mouse genome (29), and the de-
scription of the genetic abnormalities
responsible for numerous diseases. There
is now a much better understanding of
the basic molecular pathways, proteins,
and signal transduction processes that
are present in the normal cell (Fig 3) (30).
Scientists are also beginning to elucidate,
as well, those altered processes responsi-
ble for numerous human diseases. Asso-
ciated with these developments in basic
molecular and cellular biology, the imag-
ing sciences have made advances in tech-
nologies including MR imaging, PET, and
optical imaging.

The Advent of Molecular Imaging
The term molecular imaging came into
use in the mid to late 1990s. Yet, the
subspecialty of nuclear medicine has
been providing for many years what
might be considered molecular imaging
information. With a thyroid uptake and
scan for assessment of benign and ma-
lignant thyroid disease, a radioactive
Figure 1: Glucose and FDG metabolism. (a) Transport and metabolism of glucose compared with FDG.
The normal metabolic fate of glucose is phosphorylation to glucose-6-PO4 by hexokinase. Once phosphory-
lated, glucose-6-PO4 can be used as an energy source with production of CO2 and H2O or stored in the form of
glycogen. FDG, on the other hand, is phosporylated to FDG-6-P and metabolically trapped. (b) A more de-
tailed depiction of the metabolic fate of FDG only. After the facilitated transport by GLUT-1 (K1), FDG is phos-
phorylated by hexokinase (k3). FDG-6-phosphate can neither undergo further metabolism nor diffuse out of
cells. As the dephosphorylation (k4) reaction also occurs slowly, FDG-6-phosphate is trapped intracellularly
and accumulates. ADP ⫽ adenosine diphosphate, ATP ⫽ adenosine triphosphate, F-6-PO4 ⫽ fructose-6-
phosphate, G-6-P ⫽ glucose-6-phosphatase. (Fig 1b reprinted, with permission, from reference 3.)

Radiology: Volume 244: Number 1—July 2007 41

MOLECULAR IMAGING SERIES: Molecular Imaging: Future Vision and Opportunity Hoffman and Gambhir

Figure 2
(NCI). In 1998, the NCI began describ- aging and small animal imaging centers.
ing the potential power of imaging tech- The goals of the NCI (34–36) included
niques and molecular imaging, in partic- the following: (a) to develop and vali-
ular, in the yearly NCI Bypass Budget date imaging technologies and agents
(31–36). The NCI Bypass Budget is a (eg, probes, radiopharmaceutical agents)
public document produced annually by that have the sensitivity to detect precan-
the NCI to identify for the Administra- cerous abnormalities or very small can-
tion and Congress of the U.S. govern- cers; (b) to develop imaging techniques
ment those scientific priorities on which that can help to identify the biological
Figure 2: Spectrum of imaging technologies. the budget appropriation should be properties of precancerous or cancerous
The currently available imaging technologies, to spent. Imaging was identified as an area cells that will aid the prediction of clinical
varying degrees, are used to image anatomy, of “extraordinary opportunity” in the course and response to interventions (Fig
physiology, or molecular processes. Today, CT NCI budgets from 1998 –2003. Several 4) (41,42); (c) to develop minimally inva-
and US and to a large degree MR imaging are used Requests for Applications were subse- sive imaging technologies that can be
primarily for anatomic imaging purposes, even quently announced at various points used in interventions and in assessment
though there is the capability for all three of these during that time period for In Vivo Cel- of treatment outcomes; (d) to foster in-
modalities to be used, to varying degrees, for lular and Molecular Imaging Centers, teraction and collaboration among im-
physiologic assessments. MR imaging has the known as ICMICs (35–37), and Small aging scientists and basic biologists,
capability to make some molecular imaging as- Animal Imaging Resource Programs, chemists, and physicists to help advance
sessments. PET and optical imaging, on the other
also called SAIRPs (38–40). A substan- imaging research; and (e) to create in-
hand, provide less anatomic information and are
tial financial investment has been made frastructures to advance research in de-
primarily molecular and, to a lesser degree, physi-
by the NCI in providing this important velopment, assessment, and validation
ologic imaging techniques.
infrastructure to promote molecular im- of new imaging tools, techniques, and
assessment methods.
During the past several years, the
Figure 3 NCI and many other institutes at the
National Institutes of Health—the Na-
tional Heart, Lung, and Blood Institute,
National Institute on Drug Abuse, Na-
tional Institute of Biomedical Imaging
and Bioengeneering, and the National
Institute of Mental Health— have put in
place programs to promote molecular
imaging. The NCI has provided a pro-
gram to facilitate the development of
imaging probes and contrast agents that
will facilitate molecular imaging assess-
ments of pathways in cancer. The De-
velopment of Clinical Imaging Drugs
and Enhancers (43), known as DCIDE,
program facilitates and promotes pre-
clinical development and validation of
important imaging agents, probes, and
ligands. On a competitive basis, NCI will
assist with the synthesis, testing, and
distribution of probes that are used to
image the molecular, physiologic, and
functional status of tumor tissue in the
Figure 3: The emergent integrated circuit of the cell. Progress in dissecting signaling pathways has begun human body. These infrastructure pro-
to lay out a circuitry that will likely mimic electronic integrated circuits in complexity and finesse, where tran- grams continue to the present at the
sistors are replaced by proteins (eg, kinases and phosphatases) and the electrons by phosphates and lipids, NCI. A Network for Transitional Re-
among others. In addition to the prototypical growth signaling circuit centered around Ras and coupled to a search for Optical Imaging, also called
spectrum of extracellular cues, other component circuits transmit antigrowth and differentiation signals or NTROI, is a recently funded initiative
mediate commands to live or die by apoptosis. As for the genetic reprogramming of this integrated circuit in
(44). The Network will develop consen-
cancer cells, some of the genes known to be functionally altered are in red. (Reprinted, with permission, from
sus and validation processes for transla-
reference 30.)
tional research in the newly evolving

42 Radiology: Volume 244: Number 1—July 2007

MOLECULAR IMAGING SERIES: Molecular Imaging: Future Vision and Opportunity Hoffman and Gambhir

Figure 4
discipline of optical imaging, including
optimization of emerging optical imag-
ing systems and targeted or activatable
probes. Long-term goals include devel-
opment and delivery of common or sim-
ilar platforms for measuring and ex-
tracting quantitative signatures from
endogenous molecules or molecular
probes that are cancer specific.
Soon after becoming the director of
the National Institutes of Health in May
2002, Elias A. Zerhouni, MD, convened
a series of meetings to chart a “road-
map” for medical research in the 21st
century (45–48). The purpose was to
identify major opportunities and gaps in
biomedical research that no single insti-
tute at the National Institutes of Health
could tackle alone but that the agency as
a whole must address to have the big-
gest impact on the progress of medical
research. The opportunities for discov-
eries have never been greater, but the
complexity of biology remains a chal-
Figure 4: Carcinogenesis timeline. The process of carcinogenesis is long and variable. Depending on the
lenge. The National Institutes of Health type of cancer, the timeline from initial genetic alterations in the cell to development of clinical cancer can be
is uniquely positioned to catalyze changes 40 years or more. Molecular imaging has the potential to be used much earlier than conventional anatomic
that must be made to transform our new imaging techniques in assessment of at-risk populations for altered pathways and proteins that are typically
scientific knowledge into tangible benefits overexpressed and occur long before the development of the tumor that is detectable by using standard imag-
for people (45). Several of the roadmap ing techniques. CIS ⫽ carcinoma in situ, DCIS ⫽ ductal carcinoma in situ, CIN ⫽ cervical intraepithelial neopla-
initiatives have components that are im- sia, TIS ⫽ tumor in situ, PIN ⫽ prostate intraepithelial neoplasia. (Reprinted, with permission, from reference 41.)
aging related. In the roadmap, specific ar-
eas of interest to imagers include (a) de-
velopment of high specificity and sensitiv- and importance of molecular imaging in Another indicator that molecular imag-
ity probes to improve detection and (b) a both basic and translational research, ing is assuming increasing and critical
molecular imaging and contrast agent as well as in eventual clinical care of importance in imaging occurred in Jan-
database (MICAD) (49). With regard to patients (51–54). Molecular imaging uary 2004 when the widely read and
a, this technology development program programs have been set up at most aca- respected journal Radiology (61) made
seeks to ultimately achieve a 1000-fold demic medical centers in the United molecular imaging one of its new sec-
improvement in imaging probe detec- States. Many of these programs are due tions, with the addition of three associ-
tion sensitivity and optimal specificity to funding from the NCI (35–37). ate editors who have expertise in molec-
for basic research and clinical applica- There are now two societies de- ular imaging. These changes have all oc-
tions. With regard to b, this compre- voted to molecular imaging: the Society curred within the past 5 years.
hensive database of imaging probes, for Molecular Imaging (55) and the There are now Web sites, such as
with their specificities, activities, and Academy of Molecular Imaging (56). Molecular Imaging Central (62), that al-
applications will be integrated with the Each of these societies has a respective low an individual interested in molecu-
Molecular Libraries Cheminformatics da- molecular imaging journal, Molecular lar imaging to find the most up-to-date
tabase. For more information in regard to Imaging (57) and Molecular Imaging information on molecular imaging instru-
the specific roadmap initiatives, the ap- and Biology (58). Another medical jour- mentation, meetings, research funding
propriate Web site at the National Insti- nal, the former European Journal of opportunities, and relevant review arti-
tutes of Health (46,50) may be viewed. Nuclear Medicine, is now the European cles. This site also provides a searchable
Journal of Nuclear Medicine and Molec- database of molecular imaging terms.
ular Imaging (59). The Society of Nu-
Current Recognition of Molecular clear Medicine, which publishes the
Imaging Journal of Nuclear Medicine, also now Molecular Imaging in the Near Future
Most major U.S. academic medical cen- uses the phrase Advancing Molecular Molecular imaging will allow the imag-
ters have realized the potential impact Imaging as a byline in its name (60). ing scientist and clinician to visualize

Radiology: Volume 244: Number 1—July 2007 43

MOLECULAR IMAGING SERIES: Molecular Imaging: Future Vision and Opportunity
physiology and cellular or molecular bi- relevant physiologic and oftentimes mo-
ological processes in living tissue. Cur- lecularly controlled variables such as
rently available techniques allow visual- blood flow, oxygen consumption, glu-
ization and quantitation of potentially cose metabolism, proliferation, and tis-
Figure 5
Figure 5: General principles of activatable probes. Two broad categories of molecular imaging probes.
Radiolabeled probes (for PET and single photon emission computed tomography [SPECT] imaging and auto-
radiography) produce signal continuously, before and after they interact with their targets through the decay of
the radioisotope. A time delay between injection of the probe and imaging helps to clear the untrapped probe.
Activatable probes produce signal only when they interact with their targets (eg, near-infrared fluorescent
probes for optical imaging). A time delay between injection and imaging helps to achieve sufficient levels of
activated probe at the target site. (Reprinted, with permission, from reference 2.)
Figure 6
Figure 6: Activatable fluores-
cent probe. (a) Schematic of near-
infrared fluorescence probe acti-
vation. The initial proximity of
fluorochrome molecules to each
other results in signal quenching.
After protease activation, fluoro-
chromes become detectable
(lightbulb effect). Cy ⫽ 5 cyanine
fluorochrome, MPEG ⫽ 5 me-
thoxy-polyethylene glycol, PL ⫽ 5
poly-L-lysine. (b) Light image of
LX1 tumor implanted into the
mammary fat pad of a nude
mouse. The tumor is not detect-
able. (c) False-colored near-infra-
red fluorescent image superim-
posed on the white light image
shows cathepsin B/H enzyme
activity, which allows the detection
of this small tumor (arrow) in the
mammary fat pad. (Reprinted, with
permission, from references 1 and
63.)
44
Hoffman and Gambhir
sue hypoxia as they take place in living
cells and tissues. As basic scientists gain
a better understanding of the funda-
mental molecular biologic and biochem-
ical nature of various diseases, molecu-
lar imaging will be an important adjunct
in translating this knowledge into clini-
cal practice. Molecular imaging has the
potential to help to identify important
and key molecular pathway, signal trans-
duction, and receptor alteration abnor-
malities in disease. This important infor-
mation may elucidate how the disease be-
haves and will respond to certain drugs,
treatments, and therapies. The develop-
ment of new contrast agents and path-
way-specific imaging probes will allow the
in vivo elucidation of disease-altered mo-
lecular, metabolic, and specific cell cycle
functions. These developments will con-
tinue to occur across all of the conven-
tional disciplines of imaging, including
CT, MR imaging, nuclear medicine, PET,
and US. Newer techniques such as optical
imaging hold much promise for the detec-
tion and elucidation of disease and patho-
genesis at the microscopic level, poten-
tially even in situ. With continued evolu-
tion of technology, it will be possible to
visualize and quantitate the intracellular
changes as the cell transforms from nor-
mal to diseased.
With the advent of new molecular
imaging technologies and probes, it
should become possible to evaluate at-
risk populations earlier in the disease
process before the typical clinical pre-
sentation. Eventually it is anticipated
that, with molecular imaging techniques,
the actual molecular signatures of many
diseases will be visualized in vivo. The
molecular imaging specialist will be able
to visualize and determine which genes
are being expressed as abnormal RNA
and proteins in a specific disease and be
able to translate this information directly
into better clinical treatment of the pa-
tient. These advancements in molecular
imaging capabilities will allow for individ-
ualized and personalized patient treat-
ment based on the molecular character-
ization or phenotype of the disease pro-
cess in vivo. This ability to detect, through
imaging, the molecular changes associ-
ated with many diseases should vastly im-
prove our ability to detect, diagnose,
Radiology: Volume 244: Number 1—July 2007
MOLECULAR IMAGING SERIES: Molecular Imaging: Future Vision and Opportunity Hoffman and Gambhir

Figure 7
stage, select appropriate treatments,
monitor the effectiveness of a targeted
treatment, and determine prognosis in
many diseases.
To facilitate the development of mo-
lecular imaging technologies, there will
be associated developments in image
enhancement agents, probes, and li-
gands. These developments will im-
prove our ability to capture changes in
the biochemical makeup of cells and
other living structures. Imaging agents,
which include contrast agents, probes,
and ligands, will contribute to improved
image formation in one of three ways:
(a) They will localize in certain body
organs or structures (anatomic localiza-
tion); (b) they will attach to specific
molecules in the body (receptor local-
ization); or (c) they will become acti-
vated by certain biochemical or physical
conditions, such as the presence of a
specific enzyme in the cell (activatable
agents) (1,2) (Figs 5, 6). Studies using
these various molecular imaging probes
are being done now in animal models,
and it is only a matter of time before
these techniques and probes will be
tested in man. It is anticipated that con-
trast agents and imaging probes of the
future will be capable of revealing the
Figure 7: Small-animal imaging. Multiple imaging modalities are available for small-animal molecular
functional and molecular characteristics imaging. Shown are views of typical instruments available and illustrative examples of the variety of images
of diseases that determine clinical be- that can be obtained with these modalities. A, Coronal whole-body micro-PET image of a rat injected with FDG
havior at earlier time points. There will shows uptake of tracer in tissues that include muscle, heart, and brain and accumulation in bladder owing to
also be the capability to determine ear- renal clearance. B, Coronal micro-CT image of a mouse abdomen after intravenous injection of iodinated
lier responses to therapy and make ap- contrast medium. C, Coronal micro-SPECT image of mouse abdominal and pelvic regions after injection of
propriate changes if the therapy is inef- technetium 99m–methylene diphosphonate shows spine, pelvis, tail vertebrae, femora, and knee joints owing
fective. to accumulation of tracer in bone. D, Optical reflectance fluorescence image of a mouse shows green fluores-
Animal models of disease will make cent protein fluorescence from the liver, abdomen, spine, and brain. The mouse contains green fluorescent
it possible to perform certain kinds of protein– expressing tumor cells that have spread to various sites. (Images courtesy of Dr Hoffman, Antican-
studies that are difficult, if not impossi- cer.) E, Coronal T2-weighted micro–MR image of a mouse brain. F, Optical bioluminescence image of a
ble, to perform in humans. In addition mouse with a subcutaneous xenograft expressing Renilla luciferase in the left shoulder region after injection of
to learning more about many diseases, the substrate coelenterazine into the tail vein. Images were obtained using a cooled charge-coupled-device
research with animal models will facili- camera. The color image of visible light is superimposed on a photographic image of the mouse with a scale in
tate imaging technology improvements photons per second per square centimeter per steradian (p/s/cm2/sr). (Reprinted, with permission, from refer-
that then can be eventually applied to ence 2.)
the care of patients with many different
diseases. The advantage of noninvasive
imaging in animal models of disease is micro-US, and various optical technol- gies, such as radiation therapy and di-
the ability to perform repetitive obser- ogies (Fig 7). Furthermore, the level rected drug therapies.
vations of the biological processes un- of resolution with some small animal Molecular imaging will be a critical
derlying the disease process. This factor imaging modalities is now approach- and an integrated part of the drug devel-
is particularly important in the study of ing the size of individual cells. Imaging opment process (20,22–26). It is envi-
malignancy (38–40). Small animal imag- in animals also will help in the assess- sioned that molecular imaging could po-
ing technologies now include micro-MR, ment of the effectiveness of new in- tentially shorten the time line for drug
micro-CT, micro-SPECT, micro-PET, struments and therapeutic technolo- approval and lessen the cost because of

Radiology: Volume 244: Number 1—July 2007 45

MOLECULAR IMAGING SERIES: Molecular Imaging: Future Vision and Opportunity
expedited and more direct measure-
ment of drug effects in the body (20).
The potential importance of molecu-
lar imaging for the practice of radiology
has been noted (17). Molecular imaging
will assume an ever more important
role in furthering our understanding of
human disease and patient care in the
future (10–14,17,64). Newly developed
molecular imaging techniques will allow
visualization and quantitation of rele-
vant molecular and physiologic variables,
such as altered cellular metabolism and
proliferation (65), gene expression (66–
68), protein-protein interactions (69–73),
and enzymatic expression, that contrib-
ute to human disease. Clinically relevant
assays, such as determination of protein-
protein interactions, assessment of tissue
hypoxia, noninvasive imaging assessment
of gene expression, and assessment of en-
zymatic function, will be routinely per-
formed noninvasively by using molecular
imaging techniques.
Summary
Over the next several months, we hope
to provide the readership of Radiology
with a vision of why molecular imaging
will be important from both a research
and clinical perspective. We wish to in-
form the practicing radiologist about
the promise of molecular imaging and
how it has the potential to revolutionize
clinical imaging as we know it. As radi-
ologists and imaging scientists, it should
be our goal to provide the most critical
and relevant information required for
the care and management of patients.
Molecular imaging has the potential to
provide information that will be some of
the most critical and important informa-
tion possible. That will be in the form of
a noninvasive in vivo imaging assess-
ment of the basic molecular biologic
characterization of disease.
References
1. Weissleder R, Mahmood U. Molecular imag-
ing. Radiology 2001;219:316 –333.
2. Massoud TF, Gambhir SS. Molecular imaging
in living subjects: seeing fundamental biologi-
cal processes in a new light. Genes Dev 2003;
17:545–580.
3. Kelloff GJ, Hoffman JM, Johnson B, et al.
46
Progress and promise of FDG-PET imaging for
cancer patient management and oncologic
drug development. Clin Cancer Res 2005;
11(8):2785–2808.
4. Hicks RJ. The role of PET in monitoring ther-
apy. Cancer Imaging 2005;5(1):51–57.
5. The market for PET radiopharmaceuticals &
PET imaging. Bio-Tech report no. 200. Bio-
Tech Systems Web site. http://biotechsystems
.com/reports/200/default.asp. Accessed April
9, 2006.
6. Warburg O. The metabolism of tumors. New
York, NY: Richard R. Smith, 1931; 1–129.
7. Weber G. Enzymology of cancer cells. II.
N Engl J Med 1977;296(10):541–551.
8. Phelps ME, Huang SC, Hoffman EJ, Selin C,
Sokoloff L, Kuhl DE. Tomographic measure-
ment of local cerebral glucose metabolic rate
in humans with (F-18)2-fluoro-2-deoxy-D-
glucose: validation of method. Ann Neurol
1979;6(5):371–388.
9. Gambhir SS, Czernin J, Schwimmer J, Silver-
man DH, Coleman RE, Phelps ME. A tabu-
lated summary of the FDG PET literature.
J Nucl Med 2001;42(5 suppl):1S–93S.
10. Jaffer FA, Weissleder R. Molecular imaging in
the clinical arena. JAMA 2005;293(7):855–
862.
11. Jager PL, de Korte MA, Lub-de Hooge MN, et
al. Molecular imaging: what can be used to-
day. Cancer Imaging 2005;5(spec no. A):S27–
S32.
12. Cyrus T, Winter PM, Caruthers SD, Wickline
SA, Lanza GM. Magnetic resonance nanopar-
ticles for cardiovascular molecular imaging
and therapy. Expert Rev Cardiovasc Ther
2005;3(4):705–715.
13. Pomper MG. Translational molecular imaging
for cancer. Cancer Imaging 2005;5(spec no.
A):S16 –S26.
14. Landini L, Santarelli MF, Positano V, Leone A.
Molecular imaging: its application in cardio-
vascular diagnosis. Curr Pharm Des 2005;
11(17):2225–2234.
15. Choy G, Choyke P, Libutti SK. Current ad-
vances in molecular imaging: noninvasive in
vivo bioluminescent and fluorescent optical
imaging in cancer research. Mol Imaging
2003;2(4):303–312.
16. Gambhir SS. Molecular imaging of cancer
with positron emission tomography. Nat Rev
Cancer 2002;2(9):683– 693.
17. Hillman BJ, Neiman HI. Translating molecular
imaging research into radiologic practice:
summary of the proceedings of the American
College of Radiology Colloquium, April 22–24,
2001. Radiology 2002;222:19 –24.
18. Pomper MG. Molecular imaging: an overview.
Acad Radiol 2001;8:1141–1153.
19. Luker GD, Piwnica-Worms D. Beyond the
genome: molecular imaging in vivo with PET
and SPECT. Acad Radiol 2001;8:4 –14.
20. Kelloff GJ, Krohn KA, Larson SM, et al. The
progress and promise of molecular imaging
probes in oncologic drug development. Clin
Cancer Res 2005;11(22):7967–7985.
Hoffman and Gambhir
21. Wagenaar DJ, Weissleder R, Arne Hengerer
A. Glossary of molecular imaging terminology.
Acad Radiol 2001;8:409 – 420.
22. Wang J, Maurer L. Positron emission
tomography: applications in drug discovery
and drug development. Curr Top Med Chem
2005;5(11):1053–1075.
23. Eckelman WC, Rohatagi S, Krohn KA, Vera
DR. Are there lessons to be learned from drug
development that will accelerate the use of
molecular imaging probes in the clinic? Nucl
Med Biol 2005;32(7):657– 662.
24. Rudin M. Molecular imaging: basic principles
and applications in biomedical research. Lon-
don, England: Imperial College Press, 2005;
25. Rudin M, Rausch M, Stoeckli M. Molecular
imaging in drug discovery and development:
potential and limitations of nonnuclear meth-
ods. Mol Imaging Biol 2005;7(1):5–13.
26. Rudin M, Weissleder R. Molecular imaging in
drug discovery and development. Nat Rev
Drug Discov 2003;2:123–131.
27. Therasse P, Arbuck SG, Eisenhauer EA, et al.
New guidelines to evaluate the response to
treatment in solid tumors. European Organi-
zation for Research and Treatment of Cancer,
National Cancer Institute of the United States,
National Cancer Institute of Canada. J Natl
Cancer Inst 2000;92(3):205–216.
28. Lander ES, Linton LM, Birren B, et al. Initial
sequencing and analysis of the human genome.
Nature 2001;409:860–921. http://www.genome
.gov/11006929. Published April 14, 2003; Ac-
cessed April 2, 2006.
29. Mouse Genome Sequencing Consortium; Wa-
terston RH, Lindblad-Toh K, et al. Initial se-
quencing and comparative analysis of the
mouse genome. Nature 2002;420:520 –562.
http://www.nature.com/nature/journal/v420
/n6915/full/nature01262fs.html. Published
December 5, 2002. Accessed April 15, 2006.
30. Hanahan D, Weinberg RA. The hallmarks of
cancer. Cell 2000;100:57–70.
31. Extraordinary opportunities for new invest-
ments. In: The nation’s investment in cancer
research: a budget proposal for fiscal years
1997/98. Bypass budget. National Cancer In-
stitute, Financial Management Branch Web
site. http://fmb.cancer.gov/financial/bypass
.htm. Accessed July 15, 2006.
32. Extraordinary opportunities for investment.
In: The nation’s investment in cancer
research: a budget proposal for fiscal year
1999. Bypass budget. National Cancer Insti-
tute, Financial Management Branch Web site.
http://fmb.cancer.gov/financial/attachments
/bypass_1999.pdf. Accessed July 15, 2006.
33. Extraordinary opportunities for investment.
In: The nation’s investment in cancer
research: a budget proposal for fiscal year
2000. Bypass budget. National Cancer Insti-
tute, Financial Management Branch Web site.
http://fmb.cancer.gov/financial/attachments
/bypass_2000.pdf. Accessed July 15, 2006.
34. Scientific priorities for cancer research: NCI’s
extraordinary opportunities. In: The nation’s
investment in cancer research: a budget pro-
posal for fiscal year 2001. Bypass budget. Na-
Radiology: Volume 244: Number 1—July 2007
MOLECULAR IMAGING SERIES: Molecular Imaging: Future Vision and Opportunity
tional Cancer Institute, Financial Management
Branch Web site. http://fmb.cancer.gov
/financial/attachments/bypass_2001.pdf. Ac-
cessed July 15, 2006.
35. Hoffman JM. Imaging in cancer: a National
Cancer Institute “extraordinary opportunity”.
Neoplasia 2000;2(1-2):5– 8.
36. Hoffman JM, Menkens A. Molecular imaging
in cancer: future directions and goals of the
National Cancer Institute. Acad Radiol 2000;
7(10):905–907.
37. In vivo cancer molecular imaging centers
(ICMICs). National Cancer Institute, Cancer
Imaging Program Web site. http://imaging
.cancer.gov/programsandresources/specialized
initiatives/icmics. Accessed April 15, 2006.
38. Small animal imaging resource program
(SAIRP). National Cancer Institute, Cancer
Imaging Program Web site. http://imaging
.cancer.gov/programsandresources/specialized
initiatives/SAIRP. Accessed April 15, 2006.
39. Croft BY, Hoffman JM. NCI-funded small ani-
mal imaging programs. National Cancer Insti-
tute. Acad Radiol 2001;8:372–374.
40. Hoffman JM, Croft B. Future directions in
small animal imaging. Lab Animal 2001;30(3):
32–35.
41. O’Shaughnessy JA, Kelloff GJ, Gordon GB, et
al. Treatment and prevention of intraepithe-
lial neoplasia: an important target for acceler-
ated new agent development: recommenda-
tions of the American Association for Cancer
Research Task Force on the Treatment and
Prevention of Intraepithelial Neoplasia. Clin
Cancer Res 2002;8:314 –346.
42. Kelloff GJ. Perspectives on cancer chemopre-
vention research and drug development. Adv
Cancer Res 2000;78:199 –334.
43. Development of clinical imaging drugs & en-
hancers (DCIDE). National Cancer Institute,
Cancer Imaging Program Web site. http:
//imaging.cancer.gov/programsandresources
/specializedinitiatives/dcide. Accessed April
14, 2006.
44. Network for translational research: optical
imaging (NTROI). National Cancer Institute,
Cancer Imaging Program Web site. http:
//imaging.cancer.gov/programsandresources
/specializedinitiatives/ntroi. Accessed April
14, 2006.
45. Overview of the NIH roadmap. NIH roadmap
for medical research. Office of Portfolio Anal-
ysis and Strategic Initiatives, National Insti-
tutes of Health Web site. http://nihroadmap
.nih.gov/overview.asp. Accessed April 14,
2006.
46. NIH roadmap. NIH roadmap for medical re-
search. Office of Portfolio Analysis and Strate-
gic Initiatives, National Institutes of Health
Radiology: Volume 244: Number 1—July 2007
Web site. http://nihroadmap.nih.gov/. Ac-
cessed July 14, 2006.
47. Zerhouni E. Medicine. The NIH roadmap. Sci-
ence 2003;302(5642):63–72.
48. Zerhouni EA. US biomedical research: basic,
translational, and clinical sciences. JAMA
2005;294(11):1352–1358.
49. Molecular imaging & contrast agent database.
MICAD NIH Roadmap, National Institutes of
Health. http://www.ncbi.nlm.nih.gov/books/bv
.fcgi?call⫽bv.View.ShowTOC&rid⫽micad
.TOC&depth?pi26⬎2. Accessed April 14,
2006.
50. NIH roadmap initiatives. NIH roadmap for
medical research. Office of Portfolio Analysis
and Strategic Initiatives, National Institutes of
Health. http://nihroadmap.nih.gov/initiatives
.asp. Accessed April 14, 2006.
51. Center for molecular imaging research. Cen-
ter for Molecular Imaging Research, Massa-
chusetts General Hospital, Harvard University
Web site. http://www.mgh-cmir.org/. Ac-
cessed April 15, 2006.
52. Molecular imaging program at Stanford
(MIPS). Molecular Imaging Program, Stanford
University Web site. http://mips.stanford
.edu/. Accessed April 14, 2006.
53. Background on the Center for Advanced
Biomedical Imaging Research. News back-
grounders. The University of Texas MD
Anderson Cancer Center Web site. http://www
.mdanderson.org/departments/newsroom
/display.cfm?id⫽ffd8860c-7f0c-49c5-b7ff27d9
deecdc45&method⫽displayfull&pn⫽7816f628-
61d7-4b3c-88e76eac5072a6fe. Accessed April
15, 2006.
54. Integrated science, innovative technology: this
is the Crump institute. Crump Institute for
Molecular Imaging Web site. http://www
.crump.ucla.edu/. Accessed April 15, 2006.
55. The Society for Molecular Imaging Web site.
http://www.molecularimaging.org/. Accessed
April 15, 2006.
56. Academy of Molecular Imaging Web site.
http://www.ami-imaging.org/public/journal
.htm. Accessed April 15, 2006.
57. Molecular Imaging Web site. http://www
.journalsoft.com/molecularimaging/journal
/index.php. Accessed April 15, 2006.
58. Molecular Imaging and Biology Web site. http:
//www.ami-imaging.org/public/journal.htm.
Accessed April 15, 2006.
59. European Journal of Nuclear Medicine and
Molecular Imaging Web site. http://www
.springer.com/sgw/cda/frontpage/0,11855,
4-0-70-1038116-detailsPage%253Djournal%
257Cdescription%257Cdescription,00.html?
Hoffman and Gambhir
referer⫽www.springer.com%2Fjournal%
2F00259%2Fabout. Accessed April 15, 2006.
60. Society of Nuclear Medicine Web site. http:
//interactive.snm.org/. Accessed April 15,
2006. The Journal of Nuclear Medicine Web
site. http://jnm.snmjournals.org/. Accessed
April 15, 2006.
61. Radiology Web site http://radiology.rsnajnls
.org/. Accessed April 15, 2006.
62. Molecular Imaging Central Web site. http:
//www.mi-central.org/. Accessed April 15,
2006.
63. Weissleder R, Tung CH, Mahmood U, Bog-
danov A Jr. In vivo imaging of tumors with
protease-activated near-infrared fluorescent
probes. Nat Biotechnol 1999;17:375–378.
64. Blasberg RG. Molecular imaging and cancer.
Mol Cancer Ther 2003;2(3):335–343.
65. Krohn KA, Mankoff DA, Eary JF. Imaging
cellular proliferation as a measure of response
to therapy. J Clin Pharmacol 2001;(suppl):
96S–103S.
66. Gambhir SS, Barrio JR, Herschman HR,
Phelps ME. Imaging gene expression: princi-
ples and assays. J Nucl Cardiol 1999;6(2):
219 –233.
67. Sharma V, Luker GD, Piwnica-Worms D. Mo-
lecular imaging of gene expression and protein
function in vivo with PET and SPECT. J Magn
Reson Imaging 2002;16(4):336 –351.
68. Blasberg R. Imaging gene expression and en-
dogenous molecular processes: molecular im-
aging. J Cereb Blood Flow Metab 2002;
22(10):1157–1164.
69. Luker GD, Sharma V, Pica CM, et al. Nonin-
vasive imaging of protein-protein interactions
in living animals. Proc Natl Acad Sci U S A
2002;99:6961– 6966.
70. Luker GD, Sharma V, Piwnica-Worms D. Vi-
sualizing protein-protein interactions in living
animals. Methods 2003;29(1):110 –122.
71. Paulmurugan R, Massoud TF, Huang J, Gam-
bhir SS. Molecular imaging of drug-modulated
protein-protein interactions in living subjects.
Cancer Res 2004;64(6):2113–2119.
72. Paulmurugan R, Umezawa Y, Gambhir SS.
Noninvasive imaging of protein-protein inter-
actions in living subjects by using reporter
protein complementation and reconstitution
strategies. Proc Natl Acad Sci U S A 2002;
99(24):15608 –15609.
73. Ray P, Pimenta H, Paulmurugan R, et al. Non-
invasive quantitative imaging of protein-pro-
tein interactions in living subjects. Proc Natl
Acad Sci U S A 2002;99(5):3105–3110.
47