Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5255_Библиотеки_им_академика_М_И_Перельмана
.pdf
Radionuclides in Medicine and Research222
nuclide is within the permissible limit, necessitates such restrictions. Further, the generators for
212
Bi and
213
Bi are not yet available commercially and separation of the parent nuclides from
long lived precursors is also a challenging task.
90
Y is identified as an excellent therapeutic nuclide for treatment of large lesions, despite
absence of gamma rays for imaging or dosimetry estimations. The possibility to access 90Y, the
daughter product of 90Sr, from a long lived generator is one of the major advantages in its
widespread use and several strategies for making 90Sr-90Y generator have been reported (9).
However, due to the avid bone seeking property of long lived 90Sr, the limit for 90Sr in 90Y meant
for human use should not result in more than 74 kBq (2 Ci) body burden. In most targeted
therapy using 90Y, such as labeled antibodies or peptides, a single patient dose could contain up
to 3.7 GBq (100 mCi) of the 90Y activity and often multiple dose treatment are given to patients
with extensive disease. In such a case, the level of 90Sr would have to be well below 10–4% of
90
Y, allowing for the time lag between preparation of the radiopharmaceutical and its administration
into the patient. In view of the nature of radiation emissions, the reliable quantitation of such
very low levels of pure beta emitters is a very challenging task, well beyond the scope of a
normal hospital radiopharmacy. In particular, in the case of 90Sr-90Y generator, the task of
estimating parts per million (ppm) levels of 90Sr is formidable, as both 90Y and 90Sr are pure beta
emitters, and their quantitation will have to be done by liquid scintillation counting, for accuracy
as well as sensitivity. In this connection, a novel method that combines features of solvent
extraction and paper chromatography has been developed at BARC, India and is capable of
estimating 90Sr with adequate sensitivity and accuracy for QC of 90Sr-90Y generator (10).
188
Re, a congener of
from a generator, making it an attractive therapeutic nuclide. However,
successive neutron capture of
99m
Tc, emits high energy beta particles (2.12 MeV) and is available
186
W, with moderate capture cross sections, and hence can be
188
W is produced by
obtained in useful quantities only from very high flux (>1015 n/cm2/s) reactors, which are very
few in number in the world. Thus the availability of
188
W or
188W-188
Re generator is only from
few centers, such as the reactors at Dmitrovgrad, Russian Federation and at Oak Ridge National
Laboratory (ORNL), USA. Knapp (6) from ORNL has reported several developments related to
188W-188
Re generator and
188
Re based radiopharmaceuticals.
The palliative treatment of metastatic bone pain in terminal cancer patients, often crippled in
day-to-day life with intractable pain and immobility, has proven to be a phenomenal success of
nuclear medicine (11). 32P as phosphate, 89Sr as its chloride and
153
Sm and
complex etc. are the radionuclides of importance in this regard (11). The utility of
DTPA and
188
Re(V)-DMSA for therapy of neuroendocrine tumors has also been noted. Another
186
Re as phosphonate
117m
Sn(IV)-
option considered is to make use of a cocktail of two therapeutic nuclides, one short-lived and
another longer-lived (such as
pain relief as well as sustained respite from pain. In India, 32P as phosphate and
153
Sm+89Sr), in order to avail the dual benefit of early response of
153
Sm-EDTMP
(a phosphonate complex) available from BRIT are used, as also imported 89SrCl2. In the recent
177
times
Lu-phosphonates have also been shown to be effective and the IAEA is currently
implementing two coordinated research projects in parallel, one on the radiopharmaceutical
aspects and the other on clinical aspects, and several countries including India are participating
in collaborative development and clinical evaluation of
177
Lu-EDTMP.
Radionuclides in Medicine and Research 223
177
Lu has received a lot of attention in the past decade owing to its physical properties and
excellent production possibilities in nuclear reactors. Although the natural abundance of
176
Lu is
only 2.6%, the high thermal neutron capture cross section of 2100 barns, augmented with
epithermal neutron capture cross section, result in high yields and high specific activities of
177
Lu even in moderate flux reactors (12,13). Very high specific activities for targeted therapies
can be achieved with enriched
and receptor specific peptides, labeled with
176
Lu. Currently, several molecules, including monoclonal antibodies
177
Lu are undergoing clinical trials world over.
The merits of 33P for therapy in specific cases, due to its soft beta energy (0.25 MeV) and
nearly twice the half-life of 32P, have been recognized. The logistic problems due to higher cost
and lower availability have only precluded its full utilization. The trend in radio-nucleotides to
use more of 33P tracer (rather than 32P) for the same merits referred above, might provide the
impetus towards better availability and use of 33P in future.
Another crippling chronic disease of pain in bone joints, like rheumatoid arthritis, has been
treated with locally instilled particulate formulation containing a suitable therapeutic radionuclide.
The procedure called (radio)synoviorthesis or radiation synovectromy offers an effective alternative
to surgery, especially for patients non-responsive to conventional medical therapy. Prof. G.
Modder (14) has done pioneering work in this field and the procedure is widely practised in
Europe for efficacious treatment of patients suffering from joint pain due to rheumatoid arthritis
(RA) amongst others. This triggered the search for therapeutic radionuclides ranging from soft to
hard beta energy (Table 3), typically 0.3 MeV of
169
Er for small joints like the finger joints,
186
Re
for medium size joints and 2.27 MeV of 90Y for large joints like the knee (15). In this technique,
insoluble particulate formulations of controlled size, usually 2-5M, and in a small volume are
instilled into the inflamed synovial space of the affected joint under monitoring, with the help of
gamma camera in the case of large joints and fluoroscopy for small joints. The immobilization
of the treated joint for at least 48 hours post instillation of the radionuclide, helps prevent
leakage of activity from the joint. In view of the ease and low cost of its production, hydroxy
apatite (HA) complex and colloidal suspension of
166
Ho and
153
Sm are promising agents in
Indian context.
The prospects of radioimmunotherapy (RIT) using radiolabelled monoclonal antibodies to
tumor associated antigens and radiopeptidetherapy (RPT) using radiolabelled peptides targeted
to receptors on the lesions, are the other major exciting results shown in combating the dreadful
disease of cancer (16). While a lot of hurdles have yet to be overcome, the approaches are sound
and research efforts world over warrant the development of methods for the large scale production
of many therapeutic radionuclides of high to very high specific activity (Table 2) capable of
being attached to these biological substrates in a simple, stable manner (16,17). Radionuclide
therapy is being explored for targeting cellular and even molecular levels and exciting advances
are on the anvil. These advances have to be matched with the availability of suitable radionuclides,
including for internalized cytotoxicity.
Therapeutic efficacy depends upon the amount of absorbed radiation dose and radiosensitivity
of the irradiated target tissue. The former is influenced by such factors as the radionuclide uptake
and residence time at target site, radiation energy characteristics and target volume to be irradiated.
Radionuclides in Medicine and Research224
Radiation dosimetry aspects are an essential component of the development and acceptance of
new therapeutic applications using internally administered/loco-regionally instilled therapeutic
radionuclides. As it is generally preferable to use pure particulate emitters for therapy (that is,
bereft of gammas capable of causing damage by irradiating additional surrounding tissues), there
are difficulties in accurately estimating the absorbed dose from pure beta emitters. Radionuclides
that emit single photons that could be quantitated by SPECT or positrons for use with PET, are
necessary for reliable quantitation of uptake and retention. Thus the concept of radionuclides
analogous to the therapeutic ones, called as “surrogate radionuclides” compatible with SPECT/
PET are being used for reliable calculation of internal dosimetry e.g. use of 86Y (positron
emitter) for 90Y (Table 5).
In order to complete the coverage, a brief reference to the radionuclides suitable for
intravascular brachytherapy (IVBT) in patients undergoing percutaneous transluminal coronary
angioplasty (PTCA) is also needed (6). The irradiation of the coronary arterial lumen with ~25
Gy dose, following balloon angioplasty was considered efficacious for reduction in the incidence
rate of restenosis in these patients (The normal incidence rate of restenosis is 30-40%). 32P was
the first radionuclide successfully used in the form of 32P coated stents (‘stent based technique’).
The subsequent approaches included the ‘catheter based technique’ of using a tiny
192
Ir source or
a radioactive liquid filled balloon at low pressure. Hard beta emitters formulated as renal tubular
agents will be preferred for the latter method, e.g.
188
Re-MAG3,
188
Re-EC owing to their rapid
clearance through renal excretion (rather than perrhenate or Re-DTPA), in order to ensure more
uniform irradiation of the desired areas and at the same time minimize the absorbed dose due to
any accidental leak of radioactivity from tube joints and/or balloon rupture. The difficulties
likely to be faced in performing the procedure in hospitals while carrying out angioplasty, as
well as the emergence of alternate technique of drug-eluting stents, have led to reduction of
interest on radiation-based strategy.
Among the particle emitters, alphas have the highest LET and hence would be able to deliver
211
the dose within a very short range in the diseased tissue. Radionuclides such as
At,
212/213
Bi
(Table 2) have been avidly studied and reported. However, in-vivo targeting the labeled molecule
to the lesion is a formidable task. Further the short half lives of these isotopes and the problems
in producing them in adequate quantities have been impeding the growth of alpha particle based
therapeutic agents.
Conclusion
The efforts of the various Units of Department of Atomic Energy (DAE) in India have ensured a
high degree of reliability in the availability of reactor based radionuclides in the country. In
order to continue to cater to the emerging needs, a new high flux reactor capable of supporting
production of radionuclides by even successive neutron capture reactions (e.g.
to radioisotope production, would be needed and is planned under the next 5-year plan. Similarly,
the much-awaited commissioning of a high current 30 MeV proton cyclotron of versatile capability
in Kolkata will be another welcome addition to the existing nuclear facilities infra-structure.
Such steps would help go a long way in establishing state-of-the-art practices in nuclear medicine
(clinical and research) and bring immense benefits to the patients all over the country.
188
W) and dedicated
Radionuclides in Medicine and Research 225
References
1. Troutner DE. Chemical and physical properties of radionuclides. Nucl Med Biol 1987; 14: 171-176.
2. Ruth TJ, Pate BD, Robertson R and Porter JK. Radionuclide production for the bio-sciences. Nucl
Med Biol 1989; 16: 323-336.
3. Production technologies for molybdenum-99 and technetium-99m, IAEA-TECDOC-1065, IAEA,
Vienna, 1999.
4. Ramamoorthy N. Production and availability of
and the IAEA’s contributions in Proc. of DAE-BRNS Symposium NUCAR-2007, BARC, Mumbai,
2007; pp. 24-32.
5. Saraswathy P, Sarkar SK, Patel RR, Arora SS, Arjun G, Narasimhan DVS and Ramamoorthy N.
Evaluation of preparation and performance of gel column 99mTc generators based on zirconium
molybdate-99Mo, in IAEA-TECDOC-1029, IAEA, Vienna, 1998; pp. 385-397.
6. Knapp FF Jr. The development and use of radionuclide generators in nuclear medicine- Recent
advances and future perspectives, in Reference 5 cited above, 1998; pp. 485-495.
7. Jongen Y. High beam intensities for cyclotron based radioisotope production, in Reference 3 cited
above, 1999; pp 133-138.
8. Qaim SM. Physics, chemistry, technology and quality assurance in radionuclide production for medical
applications, in ‘Application of radiotracers in chemical, environmental and biological sciences’,
SINP, Kolkata, India, 2006; Vol. I: pp. 1-22.
9. Venkatesh M, Pandey U, Kannan R, Achuthan PV, Banerjee S, Samuel G, Pillai MRA and Ramanujam
A. Complexation Studies with 90Y from a novel 90Sr-90Y generator. Radiochimica Acta 2001; 89:
413-417.
10. Usha P, Dhami PS, Jagesia P, Pillai MRA, Venkatesh M. Anal. Chem., (In Press) 2007.
11. Coursey BM. Guest Editor, Radionuclides for bone palliation Appl. Radiat. Isot. 1998; 49: 275-356.
12. Pillai MRA, Chakraborty S, Das T, Meera V and Ramamoorthy N. Production Logistics of
radionuclide therapy. Appl Radiat Isot 2003; 59: 109-118.
13. Venkatesh M and Chakraborty S. Production of therapeutic radionuclides in medium flux research
reactors in Proc of Intnl Symposium on Trends in Radiopharmaceuticals (ISTR-2005). IAEA, Vienna
2007; (In Press).
14. Modder G. Radiosynoviorthesis, Warlich Druck und Verlagsges, Germany, 1995..
15. Deutsch E, Brodack JW and Deutsch KE. Radiation synovectomy revisited. Eur J Nucl Med 1993;
20: 1113-1127.
16. Ramamoorthy N, Meera V and Noronha OPD. Radiopharmaceuticals Scenario—1998; Highlights of
IAEA Symposium. Ind J Nucl Med 1998; 13: 95-104.
17. Srivastava SC and Mease RC. Progress in research on ligands, nuclides and techniques for labeling
monoclonal antibodies. Nucl Med Biol 1991; 18: 589-603.
99m
Tc generators and of 99Mo: Technology considerations
177
Lu for
Suggested Reading
Manual for reactor produced radioisotopes. IAEA-TECDOC-1340, IAEA, Vienna, 2003.
Therapeutic applications of radiopharmaceuticals. IAEA-TECDOC-1228, IAEA, Vienna, 2001.
Mather SJ. Current Directions in Radiopharmaceuticals Research and Development, Springer ISBN
0792342542, 1996.
Radionuclides in Medicine and Research226
Volkert WA, Goeckler WF, Ehrhardt GJ and Ketring AR. Therapeutic radionuclides: Production and
decay property considerations. J Nucl Med 1991; 32: 174-185.
Adelstein SJ and Manning FJ. Editors; “Isotopes for Medicine and the Life Sciences”, I SBN-10:0309-05190-8
Special Issue of J. Lab. Comp. Radiopharm. Vol. 50, Supplement 1, ‘Abstracts of Presentations’ at the
17th Intnl Symp on Radiopharm Sciences (ISRS), Aachen, Germany, 2007.
Radiopharmaceuticals in Clinical
Nuclear Medicine
S. Senthil Kumar, Ajay Kumar and GP Bandopadhyaya
Nuclear medicine images represent the distribution of administered radiopharmaceuticals
in the body organs. There are specific mechanisms by which radiotracers accumulate in
different organ systems. Radiopharmaceuticals are the radioactively tagged compounds in
which the concentration of radioactive compound is so small that it neither alters the metabolic
activity of the organ nor has any toxic effect. Some of the factors, which influence the
biodistribution of radiopharmaceuticals, are given below.
Physico-chemical properties of radiopharmaceuticals
Distribution and uptake of a radiopharmaceutical depends upon its physico-chemical
properties, such as molecular or particle size, charge of the molecule, pH etc. Depending
upon the size, a radiopharmaceutical will have different distribution in different vascular
beds or will be differently absorbed/filtered/diffused through different membranes. The charge
determines the solubility and/or diffusivity. Polar molecules have higher solubility in aqueous
solution, whereas non-polar molecules are more soluble in organic solvent and lipids with
more diffusivity through cell membranes.
Stability of the labeling
The stability of labeling of a radiopharmaceutical is extremely important, as its breakdown
in-vitro or in-vivo may lead to localization in non-target tissue/organs. Unstable labeling
results in altered and erroneous interpretation besides the unnecessary radiation to tissues/
organs.
Purity of the radiopharmaceutical preparation
Any kind of impurity may lead to change in biodistribution by either changing the physicochemical properties of a radiopharmaceutical or by competing with it.
22 7
228
Radiopharmaceuticals in Clinical Nuclear Medicine
Pathophysiological state of the patient
Altered physiology or pathological state may alter the biodistribution of a radiopharmaceutical
by changing the internal milieu or tissue properties.
Drugs
Drugs may affect the biodistribution of a radiopharmaceutical by altering the enzyme levels,
receptor status or by directly interacting with it (changing its physico-chemical form or
interfering with its uptake).
It can be seen that a full understanding of properties and mechanism of localization
of radiopharmaceuticals is extremely important in identifying the source of abnormal
biodistribution and in differentiating abnormality due to disease process and drug induced
artifacts. Their quality control plays a very important role.
Nuclear medicine relies on tracer principal for diagnosis and evaluation of medical
disorders. For a substance to qualify as a tracer, its chemical nature should be identical to
the systemic substance being traced. An ideal radiotracer is one in which a stable atom of
the systemic substance is replaced by a radioactive atom. Hence radiopharmaceutical, tracing
the systemic process, should contain C, N, O, or H atoms (constituent atoms of biochemical
substances). These are predominantly positron emitters and have the disadvantages of not
being easily available. It must me noted that there is hardly any radionuclide which is ideal
for all the diagnostic procedures in nuclear medicine. A variety of radionuclides are therefore
used for diagnostic investigations. Nonetheless, many of the properties of
most suitable radionuclide for diagnostic purposes in conventional nuclear medicine
procedures.
99m
Tc make it the
Properties of ideal diagnostic radiopharmaceutical
Some of the important properties of a radiopharmaceutical that make it ideal are mentioned
below.
Pure gamma emitter
In diagnostic nuclear medicine maximum information should be derived from the investigation
with minimum radiation dose to the patient. Hence pure gamma ray emitters with
monoenergetic photons with adequate penetrating power are preferred. Unattenuated photons
from the organ are detected externally for imaging. Further pure gamma emitters give much
less radiation burden to the patient, which is significantly high in the presence of particulate
radiation (alpha and beta rays).
GSPant\Newbook\15-chp\228
Radiopharmaceuticals in Clinical Nuclear Medicine
229
Energy range
Since photoelectric absorption is inversely proportional to cube of energy (1/E3), radionuclides
emitting photons that can undergo photoelectric absorption in the detector after coming out
of the patient’s body are preferred. With the commercially available NaI(Tl) crystals (with
3/8” or 5/8” thickness) energy range of 80-240 keV gives the highest photofraction and is
optimal for imaging (1). Radionuclides such as
99m
Tc,
111
In and
123
I fall in this range and are
commonly used in nuclear medicine centers world over.
Half-life
Practically a physical half-life of 1.5 times the duration of diagnostic procedure is most
desirable. Radionuclides with short half lives deliver less radiation dose to the patient so
larger quantities of radioactivity can be administered to the patient to have better counting
statistics (information density) with reasonably small radiation dose to the patients particularly
in diagnostic procedures. It is also desirable that the radiopharmaceuticals should be excreted
out of the body as quickly as possible after completion of the procedures. Therefore it is the
effective half-life that is more important than the physical one. The
are quite adequate for most of the diagnostic investigations with physical half-life of 6 h.
The effective half-life depends on the type of pharmaceutical used.
99m
Tc labeled compounds
Target to non-target ratio
This depends upon the physico-chemical characteristics of specific radiopharmaceutical. A
high target to non-target ratio (minimum of 5:1 for planar and 2:1 for SPECT) is necessary
to interpret the images (2). A systematic analysis of structure-distribution relationship (study
of effect of variation in molecular structure on biodistribution of radiopharmaceutical) can
lead to the development of radiopharmaceuticals with high target to non-target ratio. For
example,
99m
Tc-mebrofenin and
131
I-MIBG are developed based on the analysis of structure-
distribution relationship.
Chemistry of radionuclide
For conventional nuclear medicine, ability of the radionuclide to form a wide variety of
radiopharmaceuticals is essential. This is because biodistribution depends predominantly on
the physico-chemical characteristics of the Chelate (pharmaceutical component) rather than
on the radionuclide. Being a transition metal with multiple oxidation levels,
ability to bind to a large number of compounds under physiologic conditions making it one
of the most desired radiopharmaceutical. However it is known that some compounds can be
labeled only with specific radionuclide. Hence there is always a need of several radionuclides
for different diagnostic procedures.
99m
Tc has the
GSPant\Newbook\15-chp\229
230
Radiopharmaceuticals in Clinical Nuclear Medicine
Affordability and availability
Radionuclides should be available at a reasonable cost and should be readily available to the
user.
Shelf life
The shelf life of a radionuclide should be as long as possible.
Properties of ideal therapeutic radiopharmaceutical
The aim of radionuclide therapy is to achieve complete ablation of the tumor with minimal
radiation exposure to other (non target) organs. Important considerations to achieve high
target to non-target ratio are:
1. Physico-chemical properties of radiopharmaceuticals, which help in their localization
in the target tissue/organ.
2. Type of emission, energy and duration of exposure to radiation (residence time). All
these parameters are important in delivering radiation dose to the target organ and
are briefly discussed below.
Type of emission
Pure beta emitters are the most suitable radionuclides for radioablation of the tumor. Because
of their short range (mm to cm) in tissue, delivery of dose to the target tissue/organ is
reasonably high. Radionuclides with beta and gamma radiation can also be used if high
target to non-target ratio can be achieved. For the treatment of thyrotoxicosis and thyroid
cancer,
of damage to the tissue is caused by beta particles emitted from
131
I is very commonly used which emits both beta and gamma rays. More than 90%
131
I.
Energy
The desired energy of beta particles depends upon the volume of tissue to be irradiated.
Moderate to high energy particles are usually preferred except in cases where the target
size is much less than the range of particle in that tissue. In such situations low energy beta
particles such as Auger electrons are used (targeted therapy). There is no strict cut-off for
energy level (except for targeted therapy), however radionuclides with particle energy of
around 1MeV are desirable (3).
Effective half-life
Radionuclides with effective half-life of few days are commonly preferred. As the half-life
of the radionuclide increases cumulative radiation dose to the target tissue increases resulting
in better chance for ablation. However, it also increases the radiation dose to adjacent
organs. Thus a balance between efficacy and safety needs to be maintained in selecting the
GSPant\Newbook\15-chp\230
Radiopharmaceuticals in Clinical Nuclear Medicine
231
dose of radionuclide for therapy. Chances of exceeding the threshold dose to adjacent organs
with particle therapy are relatively less.
Target to non-target ratio
This is the most important parameter in the selection of radiopharmaceuticals for therapy.
While high target to non-target ratio is desirable for diagnosis, it is mandatory for therapeutic
purposes to minimize radiation exposure to non-target organs. A figure of merit is used to
express target to non-target ratio. The figure of merit is represented by T/N where T is the
dose to the target and N is the dose to the non-target organ. Physical and chemical properties
of the radiopharmaceuticals influence the figure of merit.
Availability
It is always desirable that the radiopharmaceuticals should be readily available at affordable
price to the user.
Safe work practice
Equally important is to develop good work practice while handling radiopharmaceuticals
both for diagnosis and therapy so that chances of radioactive contamination could be
minimized. Judicious use of time, distance and shielding should be done while handling
radioactivity to keep the radiation levels as low as reasonably achievable (ALARA).
Mechanism of localization of radiopharmaceuticals
The clinical utility of a radiopharmaceutical depends on its ability to concentrate in target
tissue/lesion. For a radiopharmaceutical to be useful for evaluation of functional status of an
organ, its concentration in target organ/tissue should be sufficiently high. If one wants to use
it for differential diagnosis, it has to accumulate only in the target lesion and not in the other
areas of the same organ. For example 67Ga citrate accumulates in a variety of lesions
(inflammatory, malignant and others) making it less useful in differential diagnosis. On the
other hand
99m
Tc-HMPAO-labelled WBC study reliably differentiates inflammatory from
non-inflammatory lesions, an improvement over 67Ga citrate. Still there is scope for further
improvement because the cause of inflammation cannot be established by
WBC study. Agents like
99m
Tc-labelled ciprofloxacin, believed to be useful in differentiating
99m
Tc- HMPAO
bacterial from nonbacterial inflammation, are needed to improve the specificity of diagnosis
(4).
Classification of radiopharmaceuticals
Radiopharmaceuticals are classified as substrate non-specific and substrate specific and are
discussed below in brief.
GSPant\Newbook\15-chp\231
Соседние файлы в папке Библиотека им академика М.И. Перельмана