# REDC Product Development and Cf Program Group

**Nuclear Medicine Program**

**Russ Knapp, Manager\
\
**Our research is focused on the development of improved reactor
production and processing methods to provide medical radioisotopes, the
development of new radionuclide generator systems, the design and
evaluation of new radiopharmaceuticals for applications in nuclear
medicine, oncology and interventional cardiology, and association with
Medical Cooperative Programs throughout the world for the further
preclinical testing and clinical evaluation of agents developed at ORNL.
In the United States, only ORNL has available the combined resources of
the stable isotope inventory, a High Flux Isotope Reactor (HFIR), hot
cell processing capabilities, and a wide range of support functions
required for such research. These collective resources provide unique
capabilities in nuclear medicine research and production.

The ORNL Nuclear Medicine Program has dedicated research laboratories
available for radiochemistry, synthetic chemistry, animal experiments
and target preparation, and we also have available hot cells and glove
box facilities for radioisotope processing. The ORNL High Flux Isotope
Reactor (HFIR) provides a key resource for radioisotope production for
our research program, providing a maximum steady state thermal neutron
flux of about 2.3 x 1015neutrons per square centimeter per second, which
is the highest of any reactor in the world. The versatile HFIR
irradiation positions within the core and reflector regions include an
online, hydraulically operated system which provides access to the core
of the reactor, for both short and long term irradiations. These
capabilities offer unparalleled capability for production of very large
quantities of high specific activity radioisotopes. We are currently
developing new improved processing and purification procedures and
produce a variety of radioisotopes which are of current interest in
medicine and biology, especially for cancer therapy. A key example is
multi-Curie HFIR production of tungsten-188 (from the enriched stable
isotope 186w), which is the parent of the tungsten-188/rhenium-188
generator system which we developed to provide carrier-free rhenium-188.
Rhenium-188 from our generator is used for both research and also in
over 50 clinical trials throughout the world for various forms of cancer
therapy and for coronary restenosis therapy. Other examples of
HFIR-produced medical radioisotopes include high specific activity
holmium-166 (from natural, high-purity Ho), lutetium-177 (from enriched
Lu-176), platinum-195m (from enriched Pt-194) and tin-117m (from
enriched Sn-117). Most of the enriched stable isotopes used to produce
these medical radioisotopes in HFIR are obtained from the ORNL
calutrons. Although DOE has decided not to operate the calutrons any
longer, varying amounts of these stable isotopes remain in the ORNL
inventory.

Alternate stable isotope enrichment capabilities are being considered,
as are alternate sources (primarily Russia). Our research program also
includes production of the alpha-emitting radioisotope actinium-225,
which is used in radiotherapy of cancer. Actinium-225 is routinely
extracted from the thorium-229 stock, and ORNL is currently the largest
supplier of this medical radioisotope.\
\
**Nuclear Medicine Program**

The ORNL Nuclear Medicine Research Program follows a long tradition in
developing useful diagnostic and therapeutic applications of
radioisotopes. Our research focuses on the development of medical
radioisotope processing techniques, radionuclide generator research and
the development of new tissue-specific radiopharmaceuticals for
diagnostic and therapeutic applications in nuclear medicine, oncology
and interventional cardiology. Key strengths are in the areas of
radiopharmaceutical chemistry, radiochemistry, radioisotope process
research and biomedical applications. The ORNL High Flux Isotope Reactor
(HFIR) represents an important resource which provides primarily
neutron-rich radioisotopes. We are developing new processing procedures
and also making important contributions in the development of new
radionuclide generator systems which provide radioisotopes for various
therapeutic applications in the areas of tumor therapy and diagnosis. We
are actively collaborating with a variety of programs within ORNL and at
universities, medical schools and other research institutions throughout
the world. These Medical Cooperative Programs provide an important
opportunity for further preclinical research and clinical evaluation of
new agents developed in our ORNL program. The clinical evaluation and
commercialization of new agents developed at ORNL illustrates the
important transition of our new technologies from the laboratory to
availability for routine clinical use.\
\
**Radioisotope Processing Technology and Radionuclide Generator
Research**

The ORNL HFIR is a key resource for the ORNL program. This powerful
research reactor has the highest steady-state neutron flux of any
reactor in the world. Our optimization of the reactor production and
processing of tungsten-188 and tin-117*m* are key examples of our
research which now make these important radioisotopes routinely
available. A clinical prototype alumina-based tungsten-188/rhenium-188
generator has been developed, optimized for clinical use and a new
efficient process for rhenium-188 concentration developed and patented.
This process was initially licensed to Mallinckrodt Medical in 1997 and
a Cooperative Research and Development Agreement (CRADA) was established
for evaluation of rhenium-188 and rhenium-186 for inhibition of arterial
restenosis after balloon angioplasty. A variety of physician-approved
clinical protocols are in progress for use of rhenium-188 for restenosis
therapy and bone pain palliation and generators are routinely provided
through the ORNL Isotope Business Office. Production of tin-117*m* in
the HFIR has also been optimized and this radioisotope has been provided
for clinical trials for Sn-117m-DTPA for bone pain palliation.
Bismuth-213 is available from the actinium-225/bismuth-213 generator and
the actinium-225 parent is provided routinely for sale from ORNL.\
\
**Development and Testing of New Tissue-Specific Radiopharmaceuticals**

The development and testing of new tissue-specific radiopharmaceuticals
for in vivo nuclear imaging and therapeutic applications are important
research areas. A variety of agents are currently being developed for
tumor therapy, which are being evaluated in animal models and have shown
good therapeutic effectiveness (See following sections describing
rhenium-188 and bismuth-213). A key example of a diagnostic agent is the
research and clinical use for evaluation of myocardial viability of the
methyl-branched BMIPP fatty acid analogue which was developed in the
ORNL Nuclear Medicine Program. Iodine-125-labeled BMIPP is continuing
clinical trials at several institutions in the United States and Europe
and has been marketed in Japan by Nihon Medi-Physics, Inc., since 1993,
as an approved radiopharmaceutical named \"Cardiodine®\" for evaluation
of myocardial viability. This agent has been used in over 350,000
patient studies through 2001. More recently, BMIPP has seen a
renaissance as an important agent in cardiology research for the
evaluation of fatty acid metabolism and trafficking in conjunction with
studies of the physiology of the CD36 transport protein and the
involvement of lipoproteins and foam cells in the atherosclerotic
process. Using db/db diabetic mice, we have used BMIPP at ORNL and
demonstrated for the first time unexpected alterations in lipid
metabolism resulting from the nuclear targeting of agonists for the
nuclear peroxisomal proliferator activated receptor (PPARgamma) which
control gene expression and are used for resensitization of cells to
insulin in Type II diabetes.\
\
**The Tungsten-188/Rhenium-188 Generator System and Development and**

## Clinical Evaluation of Rhenium-188-Labeled Therapeutic Agents

We optimized the reactor production and processing of tungsten-188 and
have developed the alumina-based adsorbant-type tungsten-188/rhenium-188
generator system and developed and patented new improved methods for the
concentration of rhenium-188 bolus solutions to very high specific
volumes. Because of the long physical half-life of the tungsten-188
parent (69 days) and the long useful generator shelf-life of several
months with consistently high rhenium-188 yields (75-80 % at
equilibrium), this generator system holds great promise in providing the
cost-effective rhenium-188 radioisotope for routine use for a variety of
therapeutic applications. An important aspect of using rhenium-188 for
many applications in contrast to other therapeutic radioisotopes is the
anticipated very low costs for unit-dose, which would contribute to the
reduction of health care costs. The tungsten-188/rhenium-188 generator
is the major medical radioisotope distributed for routine sale through
the ORNL Isotope Business Office.

Several collaborative clinical programs are evaluating our
rhenium-188-labeled phosphonates for bone pain treatment, and Phase I
studies with the rhenium-188-labeled HEDP and Re(V)-DMSA agents have
shown specific targeting of skeletal metastases in patients presenting
with metastases from various cancers (See Clinical Trials section).
Protocols have also been developed initially with collaborators at
Columbia University for clinical evaluation of new rhenium-188 agents
for inhibition of restenosis following coronary angioplasty. A CRADA had
also been established with to explore various HFIR-produced
radioisotopes for introvascular brachytherapy. Protocols have also been
developed for use of particles for arthritis therapy and tumor-specific
antibodies for radioimmunotherapy.

We are also working closely with the Nuclear Medicine Section at the
International Atomic Energy Agency (IAEA) as a Research Agreement Holder
for the design and

implementation of the use of rhenium-188 for three major multi-center
clinical trials

involving the use of rhenium-188 for restenosis therapy following PTCA,
for a new

therapeutic strategy for therapy of refractory liver cancer and for
radionuclide synovectomy. The tungsten-188/rhenium-188 generator is
expected to have an

important role in the developing world in providing rhenium-188 as a
cost-effective

therapeutic radioisotopes for a variety of applications because of the
long useful

shelf-life of several months.\
\
**Alpha Emitting Radioisotopes for Tumor Therapy**

Alpha particles are of considerable interest for radioimmunotherapy
applications

since their short range in soft tissue is limited to only a few cell
diameters. The

delivery of such high energy in such a small volume, or
high-linear-energy-transfer

(LET), makes alpha particles especially well suited for targeting
micrometastatic

disease and single tumor cells such as leukemia and other blood-borne
disease. The bismuth-213 radioisotope is of special interest because of
its unique nuclear properties, which include a short 45 minute half-life
and high energy (8.4 MeV) alpha-particle emission. Its unique
availability from the actinium-225/bismuth-213 generator system makes
this radioisotope particularly well suited for medical use. The
actinium-225 is formed from radioactive decay of radium-225, the decay
product of thorium-229, which is obtained from decay of uranium-233. The
National depository of uranium-233 is at ORNL, and we have developed
effective methods for obtaining thorium-229 (half-life 7340 years) as
our feed material to routinely obtain actinium-225.

The very short 45 minute half-life of bismuth limits its use, however,
only when

attachment to a carrier molecule can be conducted very quickly and the
targeting is

rapid following intravenous administration, such as the clinical
treatment of acute

myeloid leukemia, as described later, where trials are being conducted
at the

Memorial Sloan Kettering Cancer Center in New York. The actinium-225
used for

the generators which provide the bismuth-213 for these studies is
provided from

ORNL. We are also conducting research with alpha emitting radioisotopes
such as

bismuth-213. Radioimmunotherapy with alpha particles has the advantages
of high

energy deposition (\~ 100 KeV/mm) in a short path length (\< 100 m),
which produces

significant cellular damage close to the site of radioisotope
deposition. Several

alpha-particle emitting radioisotopes have been studied for therapy and
the

antibody-targeted bismuth-213 for treatment of leukemia and intracranial
placement

of astatine-211 for adjuvant therapy after surgery for brain tumors.
Research at

ORNL has shown that monoclonal antibodies targeting bismuth-213 to lung

vasculature is also successful for the therapy of lung tumors in mice.
Bismuth-213

decays with a half-life of 46 minutes and emits very energetic alpha
particles. (\~ 8

MeV). Carrier-free bimuth-213 is obtained from the
actinium-225/bismuth-213

generator system. The actinium-225 parent (half-life = 10 days) is
obtained from

decay of thorium-229 (half-life 7,340 years). The majority of the
available

thorium-229 stock has been recovered from the nuclear waste material
which has been stored at ORNL for about 30 years. Actinium-225 batches
of up to 40 mCi are available for sale through the ORNL Isotope Business
Office on a bi-monthly schedule and smaller quantities are available on
a weekly schedule.\
\
**Medical Collaborative Programs, Technology Transfer Efforts and
Clinical Evaluation of ORNL Radiopharmaceuticals**

Collaboration with external organizations and technology transfer are
important activities that bridge the gap between development and testing
of new agents developed at ORNL and use at other institutions. Several
patents have recently been issued for new technologies developed at
ORNL. Various new agents are evaluated in collaborative programs with
Medical Cooperative Programs at clinics, universities, and other
research institutions in the United States, Europe, Australia and Asia.

## Nuclear Medicine Program Facilities and Resources

The Nuclear Medicine Program has approved procedures and laboratories
and facilities available for radiochemistry, pharmaceutical synthesis
and analytical studies. Available instrumentation includes two
multichannel analyzers, a variety of high performance liquid
chromatographs, and other laboratory instrumentation. Approved
procedures and facilities are also available for testing of targets for
reactor irradiation.

Facilities are available for housing small rodents and for conducting
injections and tissue distribution animal experiments, which has been
approved by the Association for Assessment and Accreditation of
Laboratory Animal Care International (AAALAC). All animal experiments
are conducted under procedures approved by the ORNL "Animal Care and Use
Committee."

The ORNL High Flux Isotope Reactor (HFIR) has the highest thermal
neutron flux available in the western world with versatile in core
facilities available for high flux irradiation of samples from time
periods as short as minutes up to a full operating cycle (22-24 days).
The high flux hydraulic tube positions are given priority for the
production of medical radioisotopes. Major required maintenance and
upgrades of the HFIR were conducted in 2001, which ensure continued
operation of this reactor with increased capabilities well into this
century. Hot cell facilities are available for radioisotope processing,
and Drug Master Files (DMF's) can be developed for radioisotope products
as required.

It is also expected that Current Good Manufacturing Practices (cGMP)
will be instituted at ORNL in 2002, so that radioisotope products can be
provided under cGMP's to our commercial customers. A variety of other
resources at ORNL are available in support of this program, including
target chemical processing and fabrication facilities and extensive
nuclear magnetic resonance spectroscopic and mass spectrometry
capabilities.\
\
**Summary of Clinical Studies**

Although ORNL is not licensed to distribute radioisotopes and
radiopharmaceuticals approved for human use, a number of agents and
radionuclide generators systems developed in the ORNL Nuclear Medicine
Program are distributed through the ORNL Isotopes Business Office as
radiochemicals for research and clinical studies being conducted at
institutions throughout the world. Clinical studies are conducted under

physician- sponsored protocols. The Nuclear Medicine Program offers
technical expertise and guidance on the use of medical radioisotopes to
the ORNL Isotopes Business Office. Key examples of ORNL products being
used in clinical research include the tungsten-188/rhenium-188 generator
system developed at ORNL, where rhenium-188 is being used for a variety
of therapeutic applications in over 60 clinical projects throughout the
world in the areas of nuclear medicine, oncology and interventional
cardiology, as described in the attached Tables. In addition,
bismuth-213 is being used for cancer therapy at a variety of centers and
is available from the actinium-225/bismuth-213 generator system, using
actinium-225 provided from ORNL.\
\
**New Technology at Oak Ridge National Laboratory**

Although ORNL is not licensed to distribute radioactive agents for human
use, a variety of agents and new technologies developed at ORNL are used
in physician-sponsored clinical protocols and have been commercialized
for routine use. Examples include the ORNL-developed BMIPP cardiac
imaging agent which has been commercialized by Nihon Medi-Physics in
Japan, and has been used in over 350,000 patient studies since 1993.
This agent is also used in several research protocols, and an example is
shown from the Clinic for Nuclear Medicine in Bonn, Germany.

The ORNL tungsten-188/rhenium-188 generator provides carrier-free
rhenium-188 for various therapeutic applications. The use of
liquid-filled rhenium-188 balloons for restenosis therapy after
angioplasty is being evaluated in over ten clinical sites throughout the
world and an example showing pathology results from a swine study.

Rhenium-188-labeled HEDP agent is also used been developed as a
cost-effective alternative to other agents for bone pain palliation of
metastatic disease, as shown in a study from Bonn, Germany.

Examples of other agents developed in the ORNL Program include an orally
administered radioactive fat which is use for evaluation of pancreatic
insufficiency by a simple urine test, radioactive agents for cerebral
imaging to evaluate activity of the muscarinic-cholinergic receptor, and
the use of radioactive agents for evaluation of the effects of new
insulin sensitizing drugs on lipid and glucose metabolism in animal
models of Type II diabetes.\
\
**The Tungsten-188 and Rhenium-188 Generator Information**

Although ORNL is not licensed to distribute radioactive agents approved
for human use, a variety of new agents developed in the ORNL Nuclear
Medicine Program are used in clinical trials throughout the world under
physician-sponsored protocols. A key example is the
tungsten-188/rhenium-188 generator system, which began development at
ORNL in 1986. This generator provides the carrier-free rhenium-188
therapeutic radioisotope. Because of the long 69-day half-life of the
tungsten-188 parent, the generator has a very long useful shelf-life and
provides rhenium-188 at very low costs, which is especailly important in
developing regions. We also developed at ORNL a variety of agents and

approaches for using rhenium-188 for therapeutic applications, including
rhenium-188-HEDP for bone pain palliation and rhenium-188 agents for the
inhibition of restenosis, and proposed and demonstrated for the first
time the feasibility of using liquid-filled balloons with rhenium-188.
Other applications which are being purusued by our collaborators and
customers are the use of rhenium-188-labeled peptides and antibodies for
cancer therapy and rhenium-88 particles for hepatocellular carcinoma
therapy and

treatment of arthritis.

The generators are sold from ORNL as radiochemicals, and over 60
clinical trials are in progress in over 20 countries including two multi
center trials initiated by the International Atomic Energy Agency (IAEA)
in 2001 for the treatment of hepatocellular carcinoma and for restenosis
therapy. The success of the development, promotion and widespread use of
this generator system highlights the important role the Nuclear medicine
Program continues to have in the development of important new
technology.\
\
Please direct any questions concerning nuclear medicine to:

F. F. (Russ) Knapp, Program Manager • Building 4501, MS-6229 • Oak Ridge
National Laboratory • Oak Ridge, TN 37831-6229 • Phone: 865-574-6225 •
Fax: 865-574-6226 • E-mail: knappffjr@ornl.gov