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Applications of the Carrier Free Radioisotopes of Second Transition Series Elements in the Field of Nuclear Medicine | OMICS International
ISSN: 2155-9619
Journal of Nuclear Medicine & Radiation Therapy

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Applications of the Carrier Free Radioisotopes of Second Transition Series Elements in the Field of Nuclear Medicine

Banani Mukhopadhyay1* and Krishnendu Mukhopadhyay2*

1Assistant Professor, Department of Chemistry, Women’s Christian College, College Road, Chennai 600 006, India

2Assistant Professor, Department of Environmental Health Engineering, Sri Ramachandra University, Porur, Chennai 600 116, India

Corresponding Authors:
Banani Mukhopadhyay
Assistant Professor, Department of Chemistry
Women's Christian College, College Road
Chennai 600 006, India
Tel: +91 94 4479 79 71
E-mail: [email protected]
Krishnendu Mukhopadhyay
Assistant Professor
Department of Environmental Health Engineering
Sri Ramachandra University
Porur, Chennai 600 116, India
Tel: +91 99 4100 5563
Fax: +91 44 24767008
E-mail: [email protected]

Received Date: February 21, 2011;Accepted Date: July 23, 2011; Published Date: July 25, 2011

Citation: Mukhopadhyay B, Mukhopadhyay K (2011) Applications of the Carrier Free Radioisotopes of Second Transition Series Elements in the Field of Nuclear Medicine. J Nucl Med Radiat Ther 2:115. doi:10.4172/2155-9619.1000115

Copyright: © 2011 Dalhaug A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

The carrier free radioisotopes play a vital role in the rapidly emerging fields of science and technology, emphatically in the areas of biomedical sciences. Again, the carrier free radioisotopes of transition series elements have achieved special importance due to their favourable nuclear and chemical properties, either in material research or in biomedical applications. In the present review article, the beneficial uses of some carrier free radioisotopes of the second transition series elements such as 90Y, 89Zr, 97,103Ru, 99mTc, 101mRh, 111Ag, 107,109Cd, etc. in the field of nuclear medicine has been discussed. Some probable routes for production of these radionuclides have also been indicated.

Keywords

Carrier free; Radioisotopes; Transition series; Biomedical; 90Y; 89Zr; 97,103Ru; 99mTc

Introduction

In 1934, the remarkable discovery of artificial radioactivity by Irene and Frederic Joliot Curie had added the most important step in the journey of nuclear medicine. Initially, the production of the artificial radioisotopeswas slow but, gradually it enhanced the pace by producing more than 2500 radioisotopes till now through nuclear transmutation reactions. Visualization of organs, localisation of tumours, detection of abnormalities in diagnosis, determination of metabolic pathways, introduction of radiation sources into specific sites for therapy are the different goals of nuclear medicine[1]. This can involve either the direct irradiation of the patients by an external source of radiation, or the administration of radioactively labeled drugs or radiopharmaceuticals to the patient.

The word “pharmaceutical” is related to “pharmakon”, which means poison or medicine. Usually depending upon the dosage sometimes a drug may act as a poison or as a medicine in a biological system [2]. The radiopharmaceuticals are chemical compounds containing the appropriate radioactive isotopes or radionuclides which are rendered suitable for human administration. There are certain specific criteria for a radionuclide to be used in nuclear medicine. The radionuclides having suitably short half lives and a high yield of gamma rays are used for radiopharmaceutical preparation.

The basic aim in designing radiolabeled compounds for therapy is to create a high concentration of radioactivity in the target tissues. It should be capable of delivering the desired radiation dose with minimal exposure to not-target tissue of the remainder portion of the body. Bone marrow is a very important not-target tissue. Actually to avoid excessive tissue irradiation from other emissions, e.g., from high energy β--particles during the administration of radiopharmaceuticals in living body, they are prepared with high specific activity so that a small volume is administered. High specific activity of the radioisotopes will be achieved when they are prepared in carrier Free State.

Another important point regarding the applications of radiopharmaceuticals is that the radiation dose depend both on the physical characteristics of the radionuclides and biological behavior of the radiopharmaceuticals. In other words the amount of time that a drug is useful depends on both its radioactive half-life and biological half-life.

Again, almost all the elements of transition series have more than one radioisotope having intense γ energy peaks in the detectable energy region within a wide range of half lives. The rich chemistry of the Transition Series elements, specially their variable oxidation states, ability to form various types of complexes with almost all types of ligands, is useful for making numerous radiolabeled compounds. Conjunction of these physical and chemical properties made the carrier free radionuclides of Transition Series elements almost indispensable to medical sciences especially for in vivo applications.

Keeping these facts in mind in the present review article applications of some of the carrier free radioisotopes of Second Transition Series elements such as 90Y, 89Zr, 97,103Ru, 99mTc, 101mRh, 111Ag, 107,109Cd, etc. in the field of nuclear medicine have been discussed. Again few important applications of these radioisotopes are also given in a very concise form (Table 1). Some probable production routes of these radionuclides have also been indicated in a tabular form (Table 2).

Radio-nuclides Chemical Nature Half life Decay Mode Principal g energy (keV)
(Intensity %)
Applications References
90Y   64.1h b- - Radioimmunotherapy of cancer, adjuvant to chemotherapy and bone seeking agent for bone marrow ablation 6
  DTPA       Intra-vascular radionuclide therapy (IVRANT) 8
89Zr   78.4h e 909.1 (99.01%) Antibody labelling and PET imaging 13
99mTc   6.01h IT, b- 0.004 140.5 (87.2%) SPET and labelling of leucocytes 59
  CAP       Monitoring of progression or regression of tumor during radiation therapy 48
  Apcitide       Detection of acute deep vein thrombosis 49
  Tetra-   cycline       Detection of infarcts and determination of its size 24
  Bleo-mycin       Scintigraphic visualisation of malignant tumours 29
  DTPA       Scintigraphy of kidney 31
  Stannous phylate       Hepatic imaging agent 32
  Sulfide colloid         Liver spleen scanning agent 33
  Tetro-
fosmin  
      Myocardial perfusion  imaging and tumor seeking agent 22
  MIBI       Imaging of myocardium   72
  Fosfo-mycin       Renal agent 53
  HAS       Static and dynamic imaging of vascular spaces 65
  Penicilla-mine       Potentially useful cholescintigraphic agents 68
103Ru   39.26d b- 497.05 (88.7%) Scintigraphy of patients with various types of malignant tumours 83
  Ruthenium Red       Employed in histochemistry due to its affinity towards mucopolysaccharides and tumour scanning agent 83
97Ru DTPA 2.9d e 215.70 (86.0) Cerebrospinal fluid imaging agent 82
  PIPIDA       Hepatobiliary diagnostic agent 77
  Mono-clonal antibodies       Radioimmunotherapy 76, 78
  Bleo-mycin       Cancer chemotherapeutic agent 79
  Trans-ferrin       Diagnosis of tumours 79
  DISIDA       Liver Imaging 81
111Ag   7.45d b- 342.08
(6.7)
Radioimmunotherapy 93
109Cd   462d e 88.03
(3.6)
Source of x- radiation,
Long term metabolic studies
96, 97
107Cd   6.50h e 93.1
(4.7)
Short term metabolic studies 97

Table 1: Applications of various radionuclides of Second Transition Series elements in Nuclear Medicine.

Radionuclide Source/Production Route Reference
89Zr Proton irradiation of natural yttrium: 89Y (d, 2n)89Zr a-activation of natural yttrium: 89Y (α, p3n) 89Zr 101 102
90Y β- decay of 90Sr: 90Sr image90Y 103

Table 2: Routes of production of some carrier free radioisotopes of Second Transition Series elements.

Radioisotopes of yttrium

The carrier-free 90Y isotope has been investigated as potentially useful therapeutic radioisotope in nuclear medicine. Radiation synovectomy has been pursued for a number of years as an effective alternative to chemical and surgical synovectomy for treatment of arthritis [3]. Its aim is to reduce the pain, improve mobility and preserve joint function, resulting in better quality of life for the patient. Because of its favourable physical characteristics, 90Y is used in radiation synovectomy, for treatment of rheumatoid arthritis[4]. It has a half life of 64.1h and decays to the stable 90Zr daughter product, by emission of high energy β- radiation (Emax=2.28 MeV). The beta rays have a maximum tissue range of 11 mm which is useful for the treatment of large joints such as the knees. Another major advantage is the availability of 90Y from a 90Sr/90Y generator, since the 28.8 yr half life of 90Sr makes it an attractive generator system for long-term usage [5]. 90Y is employed in radioimmunotherapy of cancers for site specific monoclonal antibody labeling [6]. 90Y obtained from a 90Sr generator, adsorbed onto resin bed has been evaluated as an adjuvant to chemotherapy [7]. Dosimetric considerations have been made on 90Y radionuclide which could be incorporated into a bone seeking agent for bone marrow ablation. 90Y–1,4,7,10-tetraazacyclododecane tetraacetic acid (90Y-DOTA) and 90Y-diethylene triamine pentaacetic acid (90Y-DTPA) complexes were studied for possible use in intravascular radionuclide therapy (IVRNT). Biodistribution of these complexes in Swiss mice showed that nearly 90% of 90Y complexes of both the ligands were excreted via urine predominantly through glomerular filtration within one hour post-injection with negligible localization in vital organs. The predominant and quick excretion of 90Y-DOTA and 90Y-DTPA through the kidneys suggest that both these complexes could be explored for use in IVRNT [8]. The 90Y-citrate is used in the biologic dosimetry of bone marrow (9). 90Y-ibritumomab tiuxetan is a novel radio immunotherapeutic agent recently approved for the treatment of relapsed or refractory low grade, follicular, or CD20+ transformed non-Hodgkin’s lymphoma. 90Y-ibritumomab tiuxetan consists of a murine monoclonal antibody covalently attached to a metal chelator, which stably chelates 111In for imaging and 90Y for therapy [10].

Though the carrier free 90Y radioisotope is widely used for therapeutic purposes it cannot be used for imaging. Consequently some reports described attempts to use γ-emitting yttrium isotopes (87Y, 86Y) to quantify the biodistribution of Y pharmaceuticals in animals as well as in humans [11]. Quantitative regional kinetics can be studied by positron emission tomography (PET). The neutron deficient 86Y radioisotope, a relatively long-lived positron emitter appears to be most promising for such PET studies [12].

Radioisotopes of zirconium

Whole body distribution and time course of diagnostic or therapeutic immuno-conjugates can be obtained noninvasively using Positron Emission Tomography (PET) and a suitable positron emitting antibody. This pharmacokinetic information can then be used to perform dosimetric calculations in order to optimize procedures involving these immuno-conjugates. Since the clearance rates of most immuno-conjugates are relatively slow, good target to blood ratios are not achieved until 24h or more after administration. Thus, commonly used PET radioisotopes, notably 18F (T1/2=110m) and 68Ga (T1/2=68m), may not be suitable as antibody labelers. 89Zr was first proposed and evaluated by Link et al. (1986) as PET antibody label since its half life (78h) is appropriate and the chemistry to attach this metal ion to antibodies using DTPA linkages is straightforward [13]. Furthermore, production of 89Zr via (p, n) reaction on 89Y (100% natural abundance) can be done using cyclotrons available to all PET centers [14].

Radioisotopes of technetium

The 99Mo/99mTc generators have wider applications in diagnostic nuclear medicine. The generator elutes contain not only 99mTc but also the long lived beta emitter 99Tc [15]. At present carrier free 99mTc radioisotope is used for more than 90% diagnostic procedures. It has multipurpose medicinal applications. During the past two decades it is serving as the backbone of nuclear medicine. Now the radiotracer 99mTc has acquired its important position in the diagnostic nuclear medicine due to its ideal photon energy (140 keV), half-life (6.02h) and availability. Recently, great attempts are being taken to synthesize 99mTc labeled radiopharmaceuticals to monitor the metabolic function of the brain and heart.

The preparation of 99mTc-labelled radiopharmaceuticals generally requires the initial reduction of 99mTc-pertechnetate, followed by reaction with added complexing agents. For this procedure, the reducing agent must be non-toxic, water soluble and must suppress 99mTc-colloid formation. The use of cuprous ion as a reducing agent for pertechnetate was described for the first time by Chervu et al. The potential usefulness of a 99mTc-Cu-DTPA complex as a renal function agent was evaluated by organ distribution studies in animals and by simultaneous continuous-infusion and single injection clearance studies. Dialysis of plasma samples obtained after the injection of 99mTc-Cu-DTPA into bilaterally nephrectomized rats indicates that only small amounts (<4%) of the complex are protein bound. This observation and the low toxicity of the copper preparation in animals appear to justify its investigation for kidney function measurement and imaging in man as well as its use as a GFR agent in animal studies [16].

The lipophilic complex of Technetium i.e., [99mTcO (L)] (where L=3,6,6,9-tetramethyl-4,8-diazaundecane-2,10-dione dioximate) is used as a cerebral blood flow imaging agent [17]. The radiopharmaceuticals currently being used for brain perfusion studies are the 99mTc complexes of the tetradentate ligands hexamethyl propylene amineoxime (HMPAO) [18] and ethyl cysteinate dimmer (ECD) [19]. Both the ligands form neutral and lipophilic complexes with 99mTc possessing an oxotechnetium core. The lipophilicities of the 99mTc complexes are conductive features which enable them to cross the blood brain barrier [20]. Polycystic kidney disease is a common hereditary disease. One of the commonest complications of this disease is infection of the renal cysts. Conventional radiology, ultrasound and CT scan is not able to clearly localize the site of infection. But it has been found that Tc-99m HMPAO labeled leukocyte scan can successfully localize the site of sepsis [21]. 99mTc-tetrofosmine is another lipophilic cationic complex that has been approved by the Food and Drug Administration as a myocardial perfusion imaging radiopharmaceutical. It has also been used as a tumour seeking agent. However its role in detecting lymphomas has not been widely investigated. Recently, Ding et al. have studied that 99mTc tetrofosmin accumulated in the three tested lymphoma cell lines, with the greatest uptake in the Hodgkin’s disease cell line. However, in comparison with 99mTc sestamibi, 99mTc tetrofosmin may not be the best radiotracer for detection of lymphoma [22]. The 99mTc-tetrofosmin chest images are potential tools for understanding multidrug resistance-mediated P-glycoprotien (MDR-Pgp) expression in non small cell lung cancer and for predicting the chemotherapeutic response to paclitaxel [23].

The use of technetium labeled radiopharmaceutical like 99mTctetracycline and 99mTc-pyrophosphate which are sequestered by acutely infarcted myocardium is discussed as a direct means of detecting an infarct and determining its size [24]. The polypeptide antibiotic drug, bleomycin [25] was recently found to have considerable therapeutic effects against epidermoid carcinomas and malignant lymphomas [26]. The polypeptide nature of bleomycin offers a unique possibility for labeling an antineoplastic drug with technetium. Such polypeptides as albumin [27] and caseidin [28] have been labeled with technetium. A trial study was undertaken to evaluate the bleomycin as a potential carrier of 99mTc for scintigraphic visualization of malignant tumors [29]. Dimercaptosuccinate has been labelled with 99mTc pertechnetate for imaging renal cortical morphology [30]. The conventional 131I-Hippuran renogram, measured with external detectors has the disadvantage of potential misinterpretation due to incorrect placement of the detectors. The problem of localising the kidneys for measurement of time activity curve corresponding to the kidney can be solved by recording curves from scintillation camera light-pen “areas of interest”. This can be done with 131I-Hippuran. Iodine-131 however is not an ideal emitter for detailed imaging with the scintillation camera due to its relatively high energy gamma radiation (Main gamma energy 364 keV). 99mTc is optimal for scintillation camera imaging, and 99mTc-DTPA provides detailed scintigrams of the kidney [31]. In 1973, Subramanian et al. introduced 99mTc-labelled stannous phylate as a hepatic imaging agent. The intravenously administered 99mTc-Sn-phylate forms an insoluble calcium salt in vivo and is actively deposited in the reticuloendothelial system, of which the hepatic Kupffer cell is the major component [32]. 99mTc-sulfide colloid has potential applications in liver spleen scan during the diagnosis of childhood sarcoidosis [33].

In order to understand the interaction of metal ions with proteins, antibodies and biocatalytic processes some research works have been reported showing the synthesis and characterisation of 99Tc nitrido complexes with cysteine (CYS), cysteine ethyl ester (CYS-OEt), etc. The presence of the Tc≡N core in the structure may induce different physicochemical properties compared to the TcO species, especially as far as lipohilicity is concerned [34]. The 99mTc nitrido complex [99mTcN (CBDTC)2] (CBDTC: N-cyclobutyl dithiocarbamato) containing [99mTcN]2+ core exhibited significant brain localization and good retention in mice, suggesting its potentiality as a brain perfusion imaging agent [35]. Biodistribution of a similar type of nitrido complex of 99mTc [99mTcN (MECHDTC)2] (MECHDTC: N-methyl, N-cyclohexyl dithiocarbamato) in mice showed that the complex accumulated in the heart and brain with high uptake suggesting its use as potential myocardial and cerebral imaging agent [36]. The technetium-labelled- N-substituted iminodiacetate compounds have been used extensively in the last 15 years to evaluate whether a jaundiced patient has intrahepatic cholestasis or extra hepatic obstruction [37]. Recently, some authors have proposed the uses of these agents, especially diisopropyliminodiacetic acid (DISIDA), for the evaluation of different aspects of hepatic and intestinal function, e. g., for intestinal mortility [38], gall blader emptying [39], diagnosis of segmental biliary obstruction [40], etc. The 99mTc pentavalent dimercaptosuccinic acid [99mTc (V)DMSA] is a useful agent for imaging thyroid medullary carcinoma [41]. On the other hand, the 99mTcN-DMSA complex would be potentially useful as a bone imaging agent which is reflected from its biodistribution in mice. Actually the biodistribution comparison in mice of the 99mTcN-DMSA complex and 99mTc-DMSA complex indicate that the presence of the 99mTc nitrido group significantly alters the biological properties of the 99mTc complex [42].

Again the generator produced radionuclide 99mTc is one of the most important radioisotopes used in Single Photon Emission Tomography (SPET). By virtue of their β+ decay the neutron deficient isotopes 92Tc (T1/2=4.4m), 93gTc (T1/2=2.7h), 94gTc (T1/2=4.88h) and 94mTc (T1/2=52m) could be used in Positron Emission Tomography (PET). The radiopharmaceuticals containing the above mentioned radioisotopes of technetium allows one to get in-vivo biokinetic data, not accessible via the 99mTc-SPET technique [43]. To quantify the biodistribution of 99mTc labelled radiopharmaceuticals in humans, it would be meaningful to combine SPECT and PET by using a positron emitting technetium isotope for the corresponding PET measurements. Taking advantage of the modern PET technique, the data obtained on the quantification of uptake kinetics and their mechanism would allow a better estimate of the diagnostic potential of new [99mTc]-compounds. Furthermore it should be possible to quantify models on the metabolic pathways of already established [99mTc]-radiopharmaceuticals [44]. In a recent study, Groshar et al. attempted to assess the diagnostic performance of quantitative SPECT of 99mTc-phytate colloid in detecting liver cirrhosis and to assess the correlation between the SPECT results and the severity of disease. For this purpose quantitative SPECT was performed on 60 patients with liver cirrhosis and 36 control patients without liver cirrhosis and the results for the two groups were compared. Cirrhotic livers had a lower total uptake than did control livers. This reduced uptake was associated with a significantly reduced percentage injected dose per cubic centimeter. The volume was similar to that of control livers. Total uptake in the spleen was significantly greater in patients with cirrhosis than in control patients because of an increased volume. Finally they have concluded that individual SPECT quantification of 99mTc-phytate colloid uptake in the liver and spleen could be used as a noninvasive method to separate normal from cirrhotic livers and to evaluate the severity of disease [45]. Dopamine is one of the key neurotransmitters and is related to brain function, including movement, emotion and cognition. Dopamine transporters (DATs), which locate on presynaptic dopamine neuron terminals, modulate dopamine concentration in the synaptic cleft by pumping dopamine back to the presynaptic neurons. DAT is considered to be a marker for the functional integrity of dopamine neurons. Many radiolabeled tropane derivatives, which can specifically bind to DAT, have been prepared and studied for in vivo imaging of DAT with PET or SPECT. [99mTc] TRODAT-1 (2β-((N, N/bis(2-mercaptoethyl)ethylene diamino) methyl), 3β-(4-chlorophenyl)tropane) is the first 99mTc-labeled imaging agent to show specific binding to DAT in the striatum of the human brain and has been demonstrated successfully for the diagnosis of DAT deficiency in neurodegenerative disorders, such as Parkinson’s disease [46].

Hematoporphyrin derivative (HpD) and other porphyrins have been shown to accumulate in tumours. A new water soluble cyclam acid porphyrins (CAP), 5,10,15,20-tetrakis [4-{4/,8/,11/-tris(carboxymethyl)- 1/-(1/4/,8/,11/-tetraazacyclotetradecane)amidomethyleneoxy}phenyl] porphyrin has been synthesized, characterized and labelled with 99mTc [47]. In vivo distribution studies were performed in C6-gliomas and N-nitroso-N-methylurea (NMU) induced mammary tumor bearing rats. Such types of studies revealed that the 99mTc-CAP has potential for detection of cancer. In addition to the use of radiolabeled CAP for detection of tumors, this agent could be employed to monitor the progression or regression of tumors following many treatment protocols before, during and after chemotherapy or radiation therapy. Like monoclonal antibodies peptides are also receptor specific. Radiolabeled receptor-specific biomolecules can detect primary sites, identify occult metastatic lesions, guide surgical intervention, stage tumors, predict efficacy of certain therapeutic agents or, when labeled with suitable radionuclides, be useful radiotherapeutic agents. During the past few years, much attention has been paid to the diagnostic applications of radiolabeled peptides. The carrier free 99mTc radionuclide is widely accessible in this field [48]. In a study, Taillefer et al. reported encouraging results in the detection of acute deep vein thrombosis (ADVT) by 99mTc-apcitide, a synthetic glycoprotein IIb/IIIa receptor-binding peptide. The authors reported a sensitivity of 86.4% in the detection of ADVT when early and delayed sets of images were analysed together [49]. 99mTc sestamibi has been widely used in nuclear oncology, as it can be taken up by many tumor types, such as breast cancer, lung cancer, bone sarcoma, soft tissue sarcoma and lymphoma [50].

99mTc-labelled ciprofloxacin, which has a 4-fluoroquinolone backbone, was developed as a biologically active radiopharmaceutical to diagnose infection, based on its broad spectrum of antibacterial activity toward not only Gram-positive but also Gram-negative bacteria [51]. The antibacterial action of ciprofloxacin is mediated via strong binding to and inhibition of bacterial DNA gynase [52]. Currently used skeletal imaging agents are based on diphosphonate ligands, which depending on reaction conditions (e.g. pH, molar ratio ligand/reductant, inert atmosphere, temperature, etc.) are mixtures of several oligomeric or polymeric 99mTc-diphosphonate complexes. Fosfomycin, the disodium salt of (-) cis 1, 2-epoxypropylphosphonic acid when labeled with Technetium-99m at pH =6.8 in the presence of stannous chloride as reductant, was described as a renal imaging agent [53]. Nevertheless, at the same molar ratio ligand/reductant, but at pH =2.5 the radiopharmaceutical has shown bone uptake. Specific imaging of the spleen (i.e., with only minimal activity in the liver) is desirable in a number of clinical situations. These include the detection of accessory spleens, the evaluation of patients with suspected congenital asplenia or polysplenia, and the evaluation of patients with suspected splenic injury. The ideal agent for splenic imaging would have the high photon yield and low radiation dose of 99mTc-sulfur colloid and the high splenic specificity of damaged 51Cr-tagged red blood cells (RBCs) [54] or 197Hgmercurihydroxypropane- labeled RBCs [55]. Theoretically, 99mTc- RBCs fulfill these requirements [56]. Recently, reproducible efficient methods of labeling RBCs with 99mTcO4 - have become available [57], and the 99mTc-RBCs may then be damaged to augment their uptake by the spleen [58]. 99mTc has also very important application in labelling leukocytes [59].

Under certain conditions globular micelles are formed in aqueous solutions of phospholipids and cholesterol [60]. These structures have been referred to as liposomes [61]. Caride et al. described the use of liposomes as a delivery system for radiopharmaceutical localization. Liposomes [99mTc-DTPA] were injected intravenously in mice and showed preferential uptake in the liver and spleen. There was a steady decline of activity in all organs, suggestive of destruction of liposomes with subsequent release of 99mTc-DTPA into the circulation. Alteration of uptake from liver to spleen, lung and bone marrow was achieved by prior loading of the circulation with nonradioactive liposomes. The authors also showed scintigraphically in dogs how 99mTc-DTPA, when administered entrapped in liposomes, follows the pattern of distribution of liposomes [62]. The clinical evaluation of 99mTc-polyethyleneglycol liposomes showed that focal infection and inflammation could be adequately imaged with this agent [63].

Radio aerosols have certain inherent advantages over 133Xe for measuring the distribution of ventilation. Radio aerosols are relatively inexpensive to produce. They can be delivered under tidal respiration, and even acutely ill patients can be adequately studied. When 99mTclabelled aerosols are employed, images of high information density, comparable to perfusion images with 99mTc-macroaggregated albumin, can be obtained. Perhaps most importantly, aerosol inhalation images can be obtained in several projections, permitting close comparison with the distribution of perfusion [64]. Human serum albumin labeled with 99mTc (99mTc-HAS) is a valuable radiopharmaceutical widely employed for static and dynamic imaging of vascular spaces [65]. Increased lung uptake of 99mTc-sulfur colloid was seen during liver scanning in a patient with falciparum malaria. This finding was due to the enhanced activity of the phagocytic cells of the reticuloendothelial system in the liver, spleen and lung found in human and experimental malaria [66]. Sentinel lymph node (SLN) biopsy has emerged as a novel approach for identifying patients with melanoma and regional nodal micrometastasis who may benefit from full nodal basin resection. To identify the pattern of tumor lymphatic drainage and the SLN, lymphoscintigraphy has been performed using primarily 99mTc-sulfur colloid (SC). Bedrosian et al. have shown that 99mTc-human serum albumin (HAS) is also an effective radiotracer for identifying sentinel lymph nodes in melanoma [67].

Several reports described thiol compounds labeled with 99mTc as potentially useful cholescintigraphic agents. Technetium-99m-labelled penicillamine (99mTc-Pen) is an example of such type of agents [68]. The excretion of technetium into the bile has been uniquely linked to 99mTc-thiol compounds, and the Tc-S coordinating bond appears to relate closely to the behavior of technetium in vivo. Technetium-99mglucoheptonate is an useful agent for brain scanning [69]. Since it was originally developed for renal imaging [70], the possibility of expanding the screening value of the brain scan at negligible cost was suggested. Immediately after brain scanning with a prospective technetium-99mglucoheptonate, the kidneys were imaged in 200 prospectively studied cases. Abnormalities were found in 22 cases (11%); they included renal metastases, renal cysts and kidney displacement or obstruction by masses. In five instances, significant abnormalities previously unknown were found. The renal contours were usually better seen than on intravenous urograms or bone scans. Most kidney studies could be completed in less than two minutes, making renal imaging worthwhile as a low-cost high-yield routine addition to brain scanning [71].

Technetium labelled isonitrile compounds are used as potential clinical miocardial perfusion agent. 99mTc-MIBI is a type of complex which has rapid lung and liver clearance and slow myocardial washout. For this reason this radiopharmaceutical is used for imaging of the myocardium [72]. Esophagitis is a common complication of gastroesophageal reflux disease (GERD). Unfortunately, an accurate diagnosis of esophagitis usually requires invasive endoscopy. Kao et al. studied and evaluated that noninvasive 99mTc-MIBI chest SPECT has excellent sensitivity and good accuracy as a screen for esophagitis [73]. In a recent study, Wakasugi et al. shown that 99mTc-MIBI scans have better sensitivity for detecting bone metastases and provide more specific complementary findings than conventional bone scans. 99mTc- MIBI accumulation attributed to bone marrow metastases may occur at an early stage, before the bone remodeling process in the surrounding bone can be detected on conventional bone scans [74]. While studying the correlation of 99mTc-mebrofenin handling with liver morphology, function and copper accumulation in Long-Evans Agouti rats, Malhi et al. suggested that 99mTc-mebrofenin scintigraphy can be useful for noninvasively monitoring disease progression and therapeutic response in Wilson’s disease [75].

Radioisotopes of ruthenium

The radionuclides of ruthenium have been investigated as potentially useful in nuclear medicine applications. The radioisotope 97Ru is an important label for both diagnostic imaging and therapeutic purpose because of its excellent physical and chemical properties [T1/2=2.9 d, 100% EC, Eγ=215.7 keV (85.8%) and 324.5 keV (10.2%), no beta emissions to contribute to the radiation dosage and a few different valence state] [76]. The [97Ru] PIPIDA [N,α-(p-isopropyl-acetanilide) iminodiacetic acid] complex has got tremendous importance as a potential hepatobiliary diagnostic agent. The above complex of ruthenium is able to provide better diagnostic information of hepatobiliary conditions in comparison to 131I- or 99mTc-labelled radiopharmaceuticals [77]. In fact 97RuPIPIDA can be successfully used for prolonged examination of liver and gallbladder disorders instead of 99mTcPIPIDA. The application of [97Ru] PIPIDA would reduce the radiation dose to two fold to the patient. The 97Ru-labelled monoclonal antibodies are produced for radioimmunotherapy [76,78]. Bleomycin (BLM) has undergone extensive investigations both as a cancer chemotherapeutic agent and as a carrier for radionuclides for imaging. 97Ru is used for the above mentioned purposes. In the diagnosis of tumours 97Ru-transferrin can also be used for the same purpose [79]. This complex can act as a positive substitute of 67Ga-citrate [80]. The 97Ru-DISIDA is a suitable agent for liver imaging [81]. [97Ru] DTPA is employed as a cerebrospinal- fluid imaging agent [82].

The ruthenium-red complex incorporating the radioisotope 103Ru can act as a tumor scanning agent. Its accumulation seems to be related to its specific binding to mucopolysaccharides. In addition, this radio compound shows potential value in the study of other pathological states involving the metabolism of mucopolysaccharides and glycoproteins. 103Ru is also used in the scintigraphy of patients with various types of malignant tumours. Head and neck tumours were identified as strongly positive in >75% of the cases. Two cases with inflammatory lesions showed positive scans with 103Ru. The ruthenium radionuclides are therefore probably not suitable for differentiating carcinoma from inflammatory states [83]. Metallocenes labeled with 103Ru have important applications in nuclear medicine diagnosis. While 103RuCl3 was evenly distributed in the body of an experimental animal, the metallocene derivatives were concentrated in the liver, lungs and spleen after i.v. injection. Metallocene labeled with 103Ru showed an extremely high kidney-to-muscle ratio of accumulation (up to 1000) [84]. 99mTc-labelled renal agents tested for comparison showed lower ratios. The radioisotope 106Ru forms a chelate with 2-3 dimercaptopropane sulfonic acid (DMPS) which has pronounced affinity for kidney [85].

Radioisotopes of rhodium

Radionuclides which emit auger and Coster-Kronig electrons following the electron capture mode of decay have been recently studied for their therapeutic potential [86]. This is due, primarily, to the discovery of the radiotoxicity resulting from the deposition of their electron energy in an extremely small volume within the DNA of the cell nucleus [87]. 101mRh is one such radionuclide that has been considered as a potential candidate for targeted radiotherapeutic use, due to its nuclear decay and chemical properties. It decays with a half life of 4.34 days by electron capture (92.8%) to stable 101Ru and by isomeric transition (7.2%) to 101Rh (T1/2=3.2 yr). Its major γ-ray emissions are 308.8 keV (87.2%) and 544 keV (4%). The 308.8 keV γ-ray is useful for in vivo monitoring with a scintillation camera. Its decay has no β-particle emissions, only Auger and Coster-Cronig electrons of energies ranging from 0.396-21.170 keV are emitted; the average depth of penetration of these being 0.01-10 μm in unit density tissue [88,89].

Radioisotopes of palladium

Interstitial implantation of radiation-emitting materials has been long recognized as effective method for tumor therapy. The advantage of interstitial implants is an opportunity to concentrate the radiation at the tumor site while minimizing radiation exposure to normal tissue. The carrier free 103Pd radioisotope has more favourable physical properties, including its low energy, rapid dose fall-off, short halflife and total cumulative dose delivery and hence it is a promising radioisotope for localized tumour treatment [90]. 103Pd brachytherapy sources are being used for interstitial brachytherapy implants in various tumour sites and particularly for prostatic carcinomas [91]. One of the key techniques for the preparation of 103Pd seed is coating onto carrier. Recently, Zhang et al. described a method for 103Pd “molecular plating” onto the surface of a silver rod [92].

Radioisotopes of silver

The use of antibodies labeled with various radionuclides to deliver therapeutic doses of radiation for human cancer treatment has now been shown to give clinically significant effects in a number of studies [93]. Such radioimminotherapy (RAIT) is dependent on several contributing factors including the radiosensitivity of the target tumor, the characteristic of the chosen antibody and, of course, the nature of the nuclide employed [94]. The carrier-free 111Ag isotope has been suggested to be more suitable for RAIT than the commonly used 131I, on the basis of its good β-emission properties, appropriate half-life of 7.5 days and much more favourable γ-ray component (342 keV, 6% for 111Ag compared with 363 keV, 82% for 131I) [95].

Radioisotopes of cadmium

As a source of x-radiation the carrier-free 109Cd has much wider applications. Two main lines with energy Eγ =22.1 keV and Eγ=24.04 keV characterize the energy of this radiation [96]. The radioisotopes of cadmium in no carrier added form have excellent applications in the metallobiochemical studies at sub cellular and molecular levels with the identification of the cadmium binding components. The long term metabolic studies are carried out with 109Cd having sufficiently long half life. On the contrary due to short half life of 107Cd it is used for short term experiment [97]. This 107Cd radioisotope can also be potentially used to label specific cadmium binding proteins from different origins which should be subsequently used for in vitro studies and structural investigations. This particular 107Cd radioisotope would also be employed to study the metabolic patterns of different isotopically labeled Cd2+ ions such as 109Cd, 115Cd and 107Cd simultaneously administered by various routes of energy/ingestion, injection and inhalation/ detecting the cadmium radioisotopes in the cellular components by high resolution computer coupled γ-ray spectrometry [98]. Identification of micro amounts of cadmium components in kidney, liver, intestine and pancreas and determination of the accumulation pattern of cadmium in different organs will be possible by the administration of 109Cd radiotracer in combination with neutron activation analysis [97].

Conclusion

Although apart from Nuclear Medicine, different imaging modalities such as Computerised Tomography using X -rays (CT scanning), Magnetic Resonance Imaging (MRI), Ultra Sound Scanning are also used, the role of Nuclear Medicine has been proven to be vital in many areas. The predictions that Nuclear Medicine Imaging will become obsolete when MRI was introduced did not come true and in fact, the current trends are to use these modalities in conjunction with each other to obtain the maximum information. The diagnostic imaging using radiopharmaceuticals has come a long way and nearly all the organs of interest can be imaged currently. The concepts of tomographic images leading to SPECT and latter high resolution SPECT have resulted in excellent pictures with 99mTc radiopharmaceutical agents. The focus in radiopharmaceutical chemistry has hence been to develop better radiopharmaceutical agents for imaging the vital organs and systems using 99mTc based radiopharmaceuticals and this aim has been achieved to a large extent. In the U. S. among the 30 million people who are hospitalised each year one in three is treated with nuclear medicine. There more than 10 million nuclear medicine procedures and more than 100 million tests are done each year with nuclear medicine. A significant number of such procedures are also performed in the rest of the world [99]. The use of radiotracers is not limited to in vivo studies but has also opened an era of “Test Tube Nuclear Medicine”. Radiolabelling of proteins and especially antibodies as tracers has introduced biotechnologies of unimaginable sensitivities of detection of molecules. The introduction of radioimmunoassay techniques in the early 1960,s by Berson and Yalow from United States and Ekin,s from U. K. have revolutionised diagnostic medicine [100].

Though the carrier free radioisotopes are preferred to the isotopic radioactivity especially for in vivo applications however the production of radiochemically pure carrier free isotopes is still a challenging and fascinating problem to the nuclear scientists. The production of carrier free nuclides by charged particle activation with the help of modern high energy particle accelerator and development of suitable radiochemical methodologies for isolation and purification of these product nuclides from the bulk target matrix will greatly meet the increasing demand for carrier free radioisotopes in medical sciences and will also enhance the scope of nuclear medicine. In spite of the enormous applications of the radiopharmaceuticals in nuclear medicine, design, development and marketing of any pharmaceutical is expensive. Preparations of radiopharmaceuticals also introduce additional variables and risk factor related to the choice of radionuclide and associated radiation.

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