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Nuclear medicine

Terminology

2-[¹⁸F]-FDG

2-[¹⁸F]fluoro-2-deoxy-D-glucose

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2-[¹⁸F]fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) was developed in 1976 as the result of collaboration between scientists of the National Institutes of Health, the University of Pennsylvania and Brookhaven National Laboratory. It was developed for a precisely specified purpose – to map glucose metabolism in the brain of living persons – which made this compound a fundamental tool for the development of many areas of human neurology. [¹⁸F]FDG was first used to determine local glucose metabolism in the brain, but the area of its use soon expanded to the study of glucose metabolism of the heart muscle, and it found significant application particularly in oncology as a tracer for monitoring the increased metabolic activity of tumour tissues. In the scientific literature, FDG is sometimes also referred to as the molecule of the century. Only a very limited circle of people know that the prototype of this molecule was assembled at the Faculty of Science of Charles University in Prague, in 1968, by Prof. Josef Pacák and Miloslav Černý. At the time, this molecule was intended to be used as a carrier of therapeutic substances into the interior of the tumour cell and to halt the glucose metabolism of tumour cells, which was supposed to lead to their gradual destruction. In 1969, the authors published an article on the synthesis of 2-deoxy-2-fluoro-D-glucose. At exactly the same time, a group from the Chester Beatty Research Institute published a similar synthesis. Their synthesis was carried out somewhat differently and completed a few months later. In later development, it was possible to label the molecule with a positron-emitting atom of the radioisotope ¹⁸F with a suitable half-life of 110 minutes, in 1978.

Properties

[¹⁸F]FDG is a glucose analogue containing the fluorine radionuclide ¹⁸F. Fluorine ¹⁸F decays by positron emission (β+) with a half-life of 109.7 minutes. For diagnostic imaging by positron emission tomography (PET), the most important are the emitted γ photons with an energy of 511 keV, formed by the interaction of the emitted positrons with electrons (so-called positron annihilation). PET diagnostics using [¹⁸F]FDG is a very advantageous method for locating neoplastic formations in almost the entire human body. It combines the excellent properties of imaging (particularly sensitivity and resolution) and of the radioactive preparation with a favourable biodistribution and a high affinity for tumour cells. The clinical application of [¹⁸F]FDG-PET has already been demonstrated in many studies for various types of malignant tumours, including cancer of the lung, head, neck, breast and rectum, as well as lymphomas, melanomas and brain tumours.

Pharmacokinetics

After intravenous administration of [¹⁸F]FDG, several biochemical processes occur in humans. Unmetabolised [¹⁸F]FDG is removed by glomerular filtration in the kidneys with incomplete reabsorption into the urine. With normally functioning kidneys, about 16 % of the administered [¹⁸F]FDG is eliminated within 60 min, and 50 % is removed after 135 min.

Cellular uptake of [¹⁸F]FDG is mediated by tissue-specific glucose transporters (GLUT), which comprise a family of 13 highly related transmembrane proteins. These proteins differ in their substrate specificities, kinetic parameters and tissue distributions. GLUT transporters transport glucose in the direction of its concentration gradient by passive transport (i.e. without the need for energy input). The most abundant are, in particular, the GLUT1 transporters, which are significantly expressed in the endothelial β-cells of the cerebral vessels and also in human erythrocytes; then the GLUT2 transporters, which are low-affinity glucose transporters present in the liver, intestines, kidneys and pancreatic β-cells; and, not least, the GLUT4 group of transporters, which are primarily expressed in the cells of striated muscle and adipose tissue. After stimulation with insulin, phosphorylation of the insulin receptor occurs and the PI3K/Akt signalling pathway is triggered, which consequently causes the translocation of glucose transporters from the intracellular space to the cytoplasmic membrane.

Intracellular [¹⁸F]FDG is subsequently phosphorylated by hexokinase to [¹⁸F]FDG-6-phosphate. The administered concentration of [¹⁸F]FDG is very low (nM), so it is not expected to significantly affect the normal metabolism of glucose, whose concentration in healthy individuals ranges from 4–6 mmol/l. [¹⁸F]FDG-6-phosphate is not further metabolised by the classical glycolytic pathway, does not pass through the pentose cycle, does not participate in glycogen synthesis, and its dephosphorylation by intracellular glucose-6-phosphatase also proceeds very slowly, so its concentration in tissues is maintained stable for several hours. After radioactive decay of [¹⁸F]FDG-6-phosphate, the non-radioactive isobar ¹⁸O is formed from ¹⁸F, which binds H+ ions from the environment, and the molecule of 2-[¹⁸O]DG-6-phosphate then passes through cellular glycolysis just like ordinary glucose.

Toxicity

In experiments on animal models, no signs of toxicity were recorded with repeated intravenous administration (14.3 mg/kg), not even after 3 weeks of follow-up. No changes were detected either microscopically or macroscopically, in the blood, urine, cerebrospinal fluid, brain, liver, heart, spleen, kidneys, lungs, ovaries or gastrointestinal tract. In humans, the usual administered dose is 0.05–1 μg/kg of body weight (200–400 MBq), in extreme cases around 10 μg/kg, which still represents 1/1000 of the concentration that appeared harmless in experimental animals. No side effects due to the toxicity or overdose of [¹⁸F]FDG have so far been recorded in the scientific literature.

Use

Oncological applications

Cardiological applications

• Viability of the heart muscle

Neurological applications

• Dementia
• Epilepsy

References

Gambhir SS, Czernin J, Schwimmer J, Silverman DH, Coleman RE, Phelps ME: A tabulated summary of the FDG PET literature.J Nucl Med42(5 Suppl):1S-93S, 2001. Review.PubMed

Woosley RL, Kim YS, Huang KC: Renal tubular transport of 2-deoxy-D-glucose in dogs and rats.J Pharmacol Exp Ther173(1):13-20, 1970.PubMed

Brian M.Gallagher, Joanna S. Fowler, Neal I. Gutterson, Robert R. MacGregor, Chung-Nan Wan and Alfred P. Wolf: Metabolic Trapping as a Principle ofRadiopharmaceutical Design: Some Factors Responsible for the Biodistribution of [¹⁸F] 2-Deoxy-2-Fluoro-D-Glucose.J Nucl Med19(10): 1154-1161, 1978.PubMed

Joost HG, BellGI, Best JD, Birnbaum MJ, Charron MJ, Chen YT, Doege H, James DE, Lodish HF, Moley KH, Moley JF, Mueckler M, Rogers S, Schürmann A, Seino S, Thorens B: Nomenclature of the GLUT/SLC2A family of sugar/polyol transport facilitators. Am J Physiol Endocrinol Metab282(4):E974-6, 2002.PubMed

Mueckler M, Hresko RC, Sato M: Structure, function and biosynthesis of GLUT1.Biochem Soc Trans25(3):951-4, 1997. Review.PubMed

Vannucci SJ, Maher F, Simpson IA: Glucose transporter proteins in brain: delivery of glucose to neurons and glia.Glia21(1):2-21, 1997. Review.PubMed

Olson AL, Pessin JE: Structure,function, and regulation of the mammalian facilitative glucose transporter gene family.Annu Rev Nutr16:235-56, 1996. Review.PubMed

Oehr P, Biersack H-J, Coleman RE: PET and PET-CT in Oncology. Springer-Verlag, Germany, 2003.

Czech Society for Oncology: http://www.linkos.cz/pacienti/index.php(5.8.2008)

Masaryk Memorial Cancer Institute: What you need to know about lung tumours. 2003

3′-[¹⁸F]FLT

¹⁸F-3′-fluoro-3′-deoxythymidine

Author of the review: This email address is being protected from spambots. You need JavaScript enabled to view it.

It took a relatively long time before it was recognised that [¹⁸F]FDG is not an entirely ideal tracer for PET diagnostics as regards the response of malignant tumours to treatment. Chemotherapy causes strong inflammation in the tumour and the surrounding tissue, which significantly increases the local accumulation of [¹⁸F]FDG and thereby makes it very difficult to evaluate the progression or regression of the treated tumour.

¹⁸F-3′-fluoro-3′-deoxythymidine ([¹⁸F]FLT), a radioactively labelled form of a pyrimidine nucleoside, was chosen as a strong candidate for monitoring the response to therapy. [¹⁸F]FLT accumulates in proliferating cells as a marker of thymidine kinase activity, which increases up to 10-fold during cell division. The non-radioactive form of FLT was first described by the group of P. Langen in 1969 as a selective inhibitor of DNA synthesis. FLT labelled with radioactive ¹⁸F was first described by I. K. Wilson in 1991 as carrier-added [¹⁸F]FLT and in 1997 by J. R. Grierson as no-carrier-added [¹⁸F]FLT. In recent years, several further approaches have been published with the aim of increasing the radiochemical yield.

[¹⁸F]FLT was first used for PET imaging in 1998 by A. F. Shields, when a specific increase in activity was observed in proliferating tissues, including tumours and bone marrow, in animals and in patients with non-small-cell lung carcinoma.

Properties

[¹⁸F]FLT is a thymidine analogue containing the fluorine radionuclide ¹⁸F in position 3′. Fluorine ¹⁸F decays by positron emission (β+) with a half-life of 109.7 minutes. For diagnostic imaging by positron emission tomography (PET), the most important are the emitted γ photons with an energy of 511 keV, formed by the interaction of the emitted positrons with electrons (so-called positron annihilation). PET diagnostics using [¹⁸F]FLT is a very advantageous method for locating areas in tissues with increased cell proliferation.

Pharmacokinetics

After [¹⁸F]FLT passes through the cell membrane by carrier-facilitated transport or by passive diffusion, [¹⁸F]FLT undergoes phosphorylation catalysed by the cytosolic isoenzyme thymidine kinase-1 (TK1). In this monophosphorylated form it is retained in the cell; the substitution in the 3′ position prevents further incorporation into DNA. It follows that PET imaging in fact detects the enzyme activity of TK1. This assumption has recently also been supported by in vitro experiments on the human lung cancer cell line A549, in which a positive correlation was found between [¹⁸F]FLT uptake and TK1 enzyme activity, from which it follows that the uptake and accumulation of [¹⁸F]FLT very probably correspond to the degree of cell proliferation. In normal cells, TK1 gene expression is a strictly regulated process with a significant increase during DNA synthesis in the S phase of the cell cycle, but in malignantly transformed cells there is a large increase in expression, which is subsequently maintained permanently throughout the entire cell cycle. Because a several-fold increase in the rate of mitosis and cell proliferation is a typical feature of malignant tumour cells, [¹⁸F]FLT is one of the tumour-specific PET tracers.

Toxicity

The radiation dosimetry and toxicity determination of FLT was performed and published by the group of H. Vesselle. All doses used for intravenous administration of [¹⁸F]FLT are calculated on the basis of patient weight using 2.59 MBq/kg (0.07 mCi/kg) and with a maximum dose of 185 MBq (5 mCi). The distribution of [¹⁸F]FLT was found to be homogeneous in every organ. The whole-body dose and the doses for individual organs are lower than or comparable with other clinically used nuclear medicine techniques. At a minimum specific activity of 3.7 GBq/μmol (0.1 Ci/μmol), a single administration of labelled and unlabelled FLT corresponds to a mass of 12.2 μg, which is a dose about 3000× lower than the amount at which any first toxic effects (e.g. peripheral neuropathy) were recorded during the clinical use of FLT as part of antiretroviral therapy (AIDS treatment). A toxicological study of [¹⁸F]FLT at the single dose used for determining tumour cell proliferation and response to therapy showed no side effects on the body; there were no changes in the function of the liver, kidneys, or neurological functions of the brain. Among blood parameters there was a slight decrease in haematocrit, haemoglobin and erythrocytes, but the explanation is the increased hydration of patients by intravenous administration of physiological saline during the examination.

Use

Oncological applications

The importance of using [¹⁸F]FLT for tumour imaging lies, firstly, in determining tumour cell proliferation as a prognostic factor for a number of tumours, and further in detecting the reduced proliferative capacity of tumour cells responding to treatment. [¹⁸F]FLT PET imaging thus becomes particularly useful for evaluating tumour response to ongoing therapy.

References

Toyohara J, Waki A, Takamatsu S, Yonekura Y, Magata Y, Fujibayashi Y: Basis of FLT as a cell proliferationmarker: comparative uptake studies with [3H]thymidine and [3H]arabinothymidine, and cell-analysis in 22 asynchronously growing tumor cell lines. Nucl Med Biol 29(3):281-7, 2002. PubMed

Barthel H, Cleij MC, Collingridge DR, Hutchinson OC, Osman S, He Q, Luthra SK, Brady F, Price PM, Aboagye EO: 3′-deoxy-3′-[¹⁸F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Cancer Res 63(13):3791-8, 2003. PubMed

Vesselle H, Grierson J, Peterson LM, Muzi M, Mankoff DA, Krohn KA: 18F-Fluorothymidine radiation dosimetry in human PET imaging studies. J Nucl Med 44(9):1482-8, 2003. PubMed

Turcotte E, Wiens LW, Grierson JR, Peterson LM, Wener MH, Vesselle H: Toxicology evaluation of radiotracerdoses of 3′-deoxy-3′-[¹⁸F]fluorothymidine (18F-FLT) for human PET imaging:Laboratory analysis of serial blood samples and comparison to previously investigated therapeutic FLT doses. BMC Nucl Med 7:3, 2007. PubMed

Salskov A, Tammisetti VS, Grierson J, Vesselle H: FLT: measuring tumor cell proliferation in vivo with positron emission tomography and 3′-deoxy-3′-[¹⁸F]fluorothymidine. Semin Nucl Med 37(6):429-39, 2007. Review. PubMed

3′-[¹⁸F]NaF

¹⁸F-sodium fluoride

Author of the review: This email address is being protected from spambots. You need JavaScript enabled to view it.

Several decades before the introduction of modern PET imaging equipment into clinical practice, it was found that [¹⁸F]NaF is an excellent radiopharmaceutical for skeletal imaging. [¹⁸F]NaF has favourable properties such as high and rapid uptake into bone accompanied by very rapid clearance from the blood, which leads to highly contrasted results in a short time. High-quality skeletal imaging can be obtained less than 1 hour after intravenous administration of the preparation.

[¹⁸F]NaF came into wide use for skeletal scintigraphy shortly after it was published by M. Blau in the early 1960s. However, the technical limitations of that time brought problems in the form of the high energy of the annihilation photons produced by the decay of ¹⁸F, and thus the impossibility of using the Anger-type γ cameras common at the time. There were also logistical problems with the production and effective transport of the radioisotope ¹⁸F with its half-life of 110 min. These technical problems, together with the widely available 99Mo/99mTc generators, strengthened the development of 99mTc bone preparations in the 1970s and 1980s. In particular, 99mTc-methylene diphosphonate (MDP) subsequently became the standard preparation for skeletal scintigraphy.

In the early 1990s, Phelps et al. took advantage of the favourable skeletal kinetics of [¹⁸F]fluoride and used it as a model for the development of whole-body PET imaging. Current PET cameras have much greater spatial resolution and significantly higher sensitivity than conventional γ cameras, which results in much higher-quality images than planar scintigraphy or SPECT. Overcoming the technical and logistical limitations associated with the use of the ¹⁸F isotope, and the increased availability of PET cameras at many nuclear medicine facilities, have renewed great interest in the use of [¹⁸F]NaF as a radiotracer for skeletal imaging.

Properties

[¹⁸F]NaF is an ionic compound of Na+ and [¹⁸F]- ions. Fluorine ¹⁸F decays by positron emission (β+) with a half-life of 109.7 minutes. For diagnostic imaging by positron emission tomography (PET), the most important are the emitted γ photons with an energy of 511 keV, formed by the interaction of the emitted positrons with electrons (so-called positron annihilation). PET diagnostics using [¹⁸F]NaF is a very advantageous method for locating areas in bone with osteoblastic (and consequently sclerotic) or osteoclastic (lytic) changes associated with oncological disease. Increased uptake of [¹⁸F]fluoride occurs in malignant bone lesions as a result of greater blood supply, increased permeability of the capillary walls and accelerated bone remodelling. However, [¹⁸F]NaF-PET imaging can also detect benign changes in the skeleton. [¹⁸F]NaF therefore cannot be classified only among the tumour-specific tracers.

Pharmacokinetics

After intravenous administration, [¹⁸F]NaF is removed from the plasma very rapidly in a biphasic exponential manner. The first phase proceeds with a half-life of 0.4 h, the second phase with a half-life of 2.6 h. Essentially all of the [¹⁸F]fluoride that is delivered to the bones by the blood is captured in them. The retention of [¹⁸F]fluoride in bone is again a biphasic process. Fluoride ions diffuse through the blood capillaries into the bone extracellular fluid, where they are chemisorbed onto the bone surface. During this first phase, [¹⁸F]- ions are exchanged for the OH- ions of hydroxyapatite [Ca10(PO4)6(OH)2] on the bone surface, forming fluoroapatite. During the second phase, [¹⁸F]- ions are incorporated into the crystalline structure of hydroxyapatite in the body of the bone. Here the [¹⁸F]- ions are retained until bone remodelling occurs. As early as 1 hour after intravenous administration of [¹⁸F]NaF, only 10 % of the administered dose can be detected in the blood. The total uptake of [¹⁸F]fluoride in bone constitutes approximately 50 % of the administered dose.

A great advantage of using [¹⁸F]NaF is the minimal binding of [¹⁸F]fluoride to serum proteins. There is a significant difference here when using [99mTc]MDP, of which about 30 % is bound to serum proteins immediately after administration and up to 70 % of the administered dose within 24 hours. This protein-bound fraction is then removed from the blood much more slowly than in the case of [¹⁸F]NaF. That is also why, when using [99mTc]MDP for skeletal scintigraphy, it is necessary to wait 3–4 h before imaging, whereas after administration of [¹⁸F]NaF higher-quality images can be obtained in less than 1 hour after administration.

Toxicity

For a proper assessment it is appropriate to compare dosimetric measurements after administration of [¹⁸F]NaF with 99mTc preparations. The half-value layer for passage through soft tissue reflects the energy of the photons emitted by the individual radioisotopes. In the case of 99mTc with a photon energy of 140 keV, the half-value layer in soft tissue is 4.6 cm; for ¹⁸F with a photon energy of 511 keV produced by positron annihilation, the half-value layer in soft tissue is 7.3 cm. This is offset by the fact that the half-life of ¹⁸F is 110 min, whereas the half-life of 99mTc is 6 h, which leads to shorter exposure times and consequently also to a reduction in the radiation dose when using [¹⁸F]NaF.

Effective doses were calculated after administration of the radiopharmaceutical at a dose of 2.11 MBq/kg for [¹⁸F]NaF and 7.40 MBq/kg for [99mTc]MDP. The results show that the estimated radiation burden for the patient with [¹⁸F]NaF-PET and [99mTc]MDP scintigraphy is almost the same.

Use

Oncological applications

One of the first well-described applications of [¹⁸F]NaF-PET was the imaging of primary bone tumours. [¹⁸F]NaF-PET imaging is further used to identify skeletal metastases of a number of primary tumours.

In patients with breast cancer, multiple skeletal metastases were detected using [¹⁸F]NaF-PET; increased uptake of [¹⁸F]fluoride was recorded in both sclerotic and lytic lesions. For lesions smaller than 3 mm on CT, reduced detectability was found with [¹⁸F]NaF-PET imaging.

With [¹⁸F]NaF-PET imaging, a much greater sensitivity was found in detecting bone lesions than with [99mTc]MDP planar scintigraphy, as documented in many studies and dozens of patients with various types of primary tumours (prostate cancer, lung cancer, thyroid cancer, breast cancer). Even higher-quality imaging using [99mTc]MDP-SPECT did not reveal, in any of the patients, further metastases that were not detected by [¹⁸F]NaF-PET. Conversely, [¹⁸F]NaF-PET found in patients several bone metastases that had not previously been detected by [99mTc]MDP planar scintigraphy or by [99mTc]MDP-SPECT. [¹⁸F]NaF-PET diagnostics also shows a significantly lower percentage of indeterminate bone lesions than [99mTc]MDP-SPECT.

There are currently not enough studies to compare the roles of [¹⁸F]NaF, [¹⁸F]FDG and other PET radiopharmaceuticals in the detection of metastatic bone lesions. The results so far suggest that [¹⁸F]FDG is more suitable for detecting metastases in the bone marrow or small osteolytic lesions – probably lesions with little or no increase in changes on the outer bone. [¹⁸F]NaF is more suitable for detecting skeletal metastases of tumours that typically have a reduced need (avidity) for FDG, such as thyroid or renal cell tumours.

A great advantage is provided by the rapid combination of PET and CT diagnostics shortly after the routine introduction of PET radiopharmaceuticals into clinical practice. [¹⁸F]NaF-PET/CT makes it possible to distinguish whether the detected changes in the skeleton are of malignant or benign nature. In all patients in whom only benign changes were detected by [¹⁸F]NaF-PET/CT, there was no clinical or imaging evidence of the development of metastases over the next 6 months.

Benign skeletal damage

Skeletal scintigraphy has become an important part of the examination of back pain in children and adolescents, predominantly young athletes. Abnormal uptake of [¹⁸F]fluoride in the spine or pelvis correlated in these patients with CT findings. In patients diagnosed by CT with a herniated disc but without signs of increased ossification, there was no corresponding increase in [¹⁸F]fluoride uptake on PET imaging. Nor were any sites with abnormal [¹⁸F]fluoride uptake found without a related CT finding.

[¹⁸F]NaF-PET is also a sensitive method for detecting focal changes in bone arising secondary to stress caused by intensive sporting activity. In cases where [¹⁸F]fluoride uptake was normal, no abnormalities were found on CT in 2/3 of patients, while in 1/3 fractures of part of a vertebra of indeterminate age (spondylolysis) were detected. Spondylolysis is a stress fracture or defect of the pars interarticularis of the vertebral arch. The risk of spondylolysis is increased precisely by certain sporting activities, such as sports with repeated hyperextension and extension with rotation, e.g. gymnastics, and with torsion against resistance, e.g. rowing. The detection of this damage using [¹⁸F]NaF-PET depends on the age of the lesion. Fresh and active lesions mostly show increased [¹⁸F]fluoride uptake; older lesions with slow healing and remodelling may not always show increased [¹⁸F]fluoride uptake at the site of interest.

Skeletal [¹⁸F]NaF-PET is also used to assess bone viability after injuries or reconstructive surgical procedures (e.g. hip joint replacement).

[¹⁸F]NaF-PET can also be used for the quantitative evaluation of bone turnover (remodelling). Quantitative [¹⁸F]NaF-PET provides a non-invasive method for measuring bone remodelling, which correlates with the results of bone histomorphometry. Quantitative [¹⁸F]NaF-PET has already been demonstrated in patients with renal osteodystrophy, postmenopausal osteoporosis and Paget's disease of bone. However, [¹⁸F]NaF-PET, as a research tool for a better understanding of bone metabolism, is still awaiting incorporation into routine clinical practice for the diagnosis and assessment of bone diseases.

Advantages of use

The advantages of using [¹⁸F]fluoride for detecting bone metastases of breast tumours, and in particular its use for monitoring the effects of therapy, are brought by a new study carried out by the team of R.K. Doot et al., the results of which were published in the Journal of Nuclear Medicine in 2010. Quantitative [¹⁸F]NaF PET analysis is able to estimate the kinetics of fluoride incorporation into bone by measuring fluoride transport, bone formation and bone remodelling. [¹⁸F]NaF PET may be a useful tool for assessing changes in bone turnover in response to therapy.

Earlier studies had already shown that the kinetic parameters describing fluoride transport to bone (K1) and the kinetics of fluoride incorporation into bone (Ki) provide clinically very useful information. The aim of the study was to determine the sensitivity, precision, accuracy and distribution of the kinetic parameters of [¹⁸F]fluoride, both in healthy bone and in bone affected by breast tumour metastases, and, on the basis of these results, to determine a parameter that could be considered a biomarker for quantifying changes in bone at the metastatic site as a response to therapy.

The study included 20 patients with bone metastases of breast cancer, both sclerotic and lytic. Most of the patients had already undergone some type of treatment (radiotherapy, chemotherapy, hormonal treatment); a few of them had not.

It was found that the parameters of [¹⁸F]fluoride transport (K1) and incorporation (Ki) differ significantly in bone metastases and in normal bone and can be determined with reasonable and sufficient precision and accuracy. The ability of dynamic [¹⁸F]NaF PET scans to quantify significant differences in both fluoride transport to bone and its incorporation into bone, between healthy individuals and patients with bone metastases, was demonstrated. This makes these [¹⁸F]NaF PET scans a very useful tool for quantifying changes in the physiology of bone metastases in response to therapy and helps to understand the effect of therapy on bone breakdown and new bone formation.

References

Blau M, Ganatra R, Bender MA: 18 F-fluoride for bone imaging. Semin Nucl Med2(1):31-7, 1972. PubMed

Blau M, Nagler W, Bender MA: Fluorine-18: a new isotope for bone scanning. J Nucl Med3:332-4, 1962.PubMed

Thrall JH: Technetium-99m labeled agents for skeletal imaging. CRC Crit Rev Clin Radiol Nucl Med 8(1):1-31, 1976. Review. PubMed

Hoh CK,Hawkins RA, Dahlbom M, Glaspy JA, Seeger LL, Choi Y, Schiepers CW, Huang SC, Satyamurthy N, Barrio JR, et al: Whole body skeletal imaging with [¹⁸F]fluoride ion and PET. J Comput Assist Tomogr17(1):34-41, 1993. PubMed

Grant FD, Fahey FH, Packard AB, Davis RT, Alavi A, Treves ST: Skeletal PET with 18F-fluoride: applying new technology to an old tracer. J Nucl Med49(1):68-78, 2008. Review. PubMed

[¹⁸F]FET

O-(2-[¹⁸F]fluoroethyl)-L-tyrosine

Author of the review: Ing. Helena Švecová, Ph.D.

Imaging of metabolism using PET (positron emission tomography) has enjoyed great interest for a long time. The most striking example is the wide use of [¹⁸F]FDG (2-[¹⁸F]fluoro-2-deoxy-D-glucose) in oncology, cardiology and neurology. In the diagnosis of tumour diseases using FDG-PET, the target is the increased anaerobic glycolysis that occurs in almost all types of tumour cells.

Another interesting target in tumour imaging is the increased protein metabolism and, as a result, the increased consumption of amino acids in tumour cells. Labelled amino acids can help to image tumours in those cases where the use of FDG has limited possibilities, for example when distinguishing inflammatory tissue from tumour growth or when imaging the brain.

O-(2-[¹⁸F]fluoroethyl)-L-tyrosine ([¹⁸F]FET) is an analogue of the amino acid tyrosine labelled with fluorine-18, which preferentially accumulates in brain tumours of the glioma type. Increased uptake of [¹⁸F]FET in gliomas occurs as a result of a higher occurrence of L-type amino acid transporters. However, unlike tyrosine, [¹⁸F]FET does not enter protein metabolism and is excreted from the body unchanged.

[¹⁸F]FET-PET is suitable for imaging the extent of gliomas, for guiding biopsy, for detecting tumour recurrence or for distinguishing recurrence from radiation necrosis. This information about the metabolism of [¹⁸F]FET is very useful for treatment planning, especially in combination with other imaging methods such as CT (computed tomography) or MRI (nuclear magnetic resonance). It is also a suitable tool for distinguishing tumour and inflammatory tissue.

Properties

[¹⁸F]FET is an analogue of tyrosine, to which an ethyl group with fluorine-18 is attached via an oxygen atom. The radionuclide ¹⁸F is a positron emitter with a half-life of 109.7 minutes, suitable for PET. PET using [¹⁸F]FET (FET-PET) is a suitable method for the diagnosis of brain tumours.

Pharmacokinetics

Natural tyrosine is not only a building block for proteins but also enters, as a precursor, into the synthesis of hormones, catecholamines and melanin. However, its fluorinated analogue [¹⁸F]FET has not been shown to participate in any of these processes. [¹⁸F]FET is relatively metabolically stable. It passes through the body largely unchanged and is excreted in the urine. Only a small part of [¹⁸F]FET is metabolised before excretion. The fact that [¹⁸F]FET is not involved in protein synthesis does not reduce its usefulness for detecting increased amino acid uptake in tumours.

The uptake of [¹⁸F]FET in tumours is controlled by a specific amino acid transport system. A number of experiments have shown that this is the L system. Other L-tyrosine analogues, such as L-[¹¹C]tyrosine or 2-[¹⁸F]fluoro-L-tyrosine, also use the same route for transport into the cell. Unlike them, however, [¹⁸F]FET probably uses only one subtype of the L transporter, namely LAT2. This would be indicated by the slight uptake of [¹⁸F]FET in muscle, where LAT2 is present, but zero uptake in inflammatory tissue, where LAT2 is not found.

In the whole-body distribution of [¹⁸F]FET in patients with a brain tumour, it was shown that [¹⁸F]FET is evenly distributed in the bloodstream within 20 minutes of intravenous administration and its concentration in the blood remains almost constant for a further 4 hours. [¹⁸F]FET does not accumulate in any organ more than corresponds to the perfusion of that organ. Only very slight uptake of [¹⁸F]FET appears in the muscles, pancreas and heart. In gliomas, [¹⁸F]FET reaches maximum uptake roughly 20 to 60 min after administration, with the ratio of activity in the tumour to activity in the surrounding brain tissue increasing over this interval for low-grade tumours, whereas for higher-grade tumours this ratio decreases.

Toxicity

In general, O-(2-[¹⁸F]fluoroethyl)-L-tyrosine is non-toxic and no side effects have so far been described in the literature. The toxicity of the inactive drug was verified in mice, where the highest administered dose was 150 µg/kg for 15 days. This dose was well tolerated by the animals without any problems.

The maximum activity of labelled [¹⁸F]FET administered in humans is up to 400 MBq, which, at a molecular weight of [¹⁸F]FET equal to 226.24 g/mol, corresponds to 1.43 ng of the drug, i.e. 0.02 ng/kg for a normal (70 kg) patient. Given these low administered amounts and the single clinical administration of the active substance, the risk associated with the chemical toxicity of the drug can be considered negligible.

Given the radionuclide ¹⁸F, the radiotoxicity of [¹⁸F]FET can be considered as for all diagnostic radiopharmaceuticals. 18F is a high-energy emitter (511 keV); on the other hand, its very short physical half-life (110 minutes) significantly reduces the radiation burden on the patient. When 370 MBq of [¹⁸F]FET is administered, the effective dose is 6.1 mSv, i.e. 16.5 µSv/MBq, which is within the range of routine nuclear medicine examinations (e.g. for [¹⁸F]FDG the effective dose is 27 µSv/MBq).

Use

Oncological applications

References

Vees H, Senthamizhchelvan S, Miralbell R, Weber DC, Ratib O, Zaidi H: Assessment of various strategies for (18)F-FET PET-guided delineation of target volumes in high-grade glioma patients. Eur J Nucl Med Mol Imaging. 2008 PubMed

Balogova S, Périé S, Kerrou K, Grahek D, Montravers F, Angelard B, Susini B, El Chater P, St Guily JL, Talbot JN: Prospective Comparison of FDG and FET PET/CT in Patients with Head and Neck Squamous Cell Carcinoma. Mol Imaging Biol 10(6):364-73, 2008. PubMed

Floeth FW, Sabel M, Stoffels G, Pauleit D, Hamacher K, Steiger HJ, Langen KJ: Prognostic value of 18F-fluoroethyl-L-tyrosine PET and MRI in small nonspecific incidental brain lesions. J Nucl Med. 49(5):730-7, 2008. PubMed

Stockhammer F, Plotkin M, Amthauer H, van Landeghem FK, Woiciechowsky C: Correlation of F-18-fluoro-ethyl-tyrosin uptake with vascular and cell density in non-contrast-enhancing gliomas. J Neurooncol 88(2):205-10, 2008. PubMed

Mehrkens JH, Pöpperl G, Rachinger W, Herms J, Seelos K, Tatsch K, Tonn JC, Kreth FW: The positive predictive value of O-(2-[¹⁸F]fluoroethyl)-L-tyrosine (FET) PET in the diagnosis of a glioma recurrence after multimodal treatment. J Neurooncol 88(1):27-35, 2008. PubMed

Pöpperl G, Kreth FW, Mehrkens JH, Herms J, Seelos K, Koch W, Gildehaus FJ, Kretzschmar HA, Tonn JC, Tatsch K: FET PET for the evaluation of untreated gliomas: correlation of FET uptake and uptake kinetics with tumour grading. Eur J Nucl Med Mol Imaging 34(12):1933-42, 2007. PubMed

Floeth FW, Pauleit D, Sabel M, Stoffels G, Reifenberger G, Riemenschneider MJ, Jansen P, Coenen HH, Steiger HJ, Langen KJ: Prognostic value of O-(2-18F-fluoroethyl)-L-tyrosine PET and MRI in low-grade glioma. J Nucl Med 48(4):519-27, 2007. PubMed

Salber D, Stoffels G, Pauleit D, Oros-Peusquens AM, Shah NJ, Klauth P, Hamacher K, Coenen HH, Langen KJ: Differential uptake of O-(2-18F-fluoroethyl)-L-tyrosine, L-3H-methionine, and 3H-deoxyglucose in brain abscesses. J Nucl Med 48(12):2056-62, 2007. PubMed

Laïque S, Egrise D, Monclus M, Schmitz F, Garcia C, Lemaire C, Luxen A, Goldman S: L-amino acid load to enhance PET differentiation between tumor and inflammation: an in vitro study on (18)F-FET uptake. Contrast Media Mol Imaging 1(5):212-20, 2006. PubMed

Langen KJ, Hamacher K, Weckesser M, Floeth F, Stoffels G, Bauer D, Coenen HH, Pauleit D: O-(2-[¹⁸F]fluoroethyl)-L-tyrosine: uptake mechanisms and clinical applications. Nucl Med Biol 33(3):287-94, 2006. Review. PubMed

Pöpperl G, Götz C, Rachinger W, Schnell O, Gildehaus FJ, Tonn JC, Tatsch K: Serial O-(2-[(18)F]fluoroethyl)-L-tyrosine PET for monitoring the effects of intracavitary radioimmunotherapy in patients with malignant glioma. Eur J Nucl Med Mol Imaging 33(7):792-800, 2006. PubMed

Pauleit D, Floeth F, Hamacher K, Riemenschneider MJ, Reifenberger G, Müller HW, Zilles K, Coenen HH, Langen KJ: O-(2-[¹⁸F]fluoroethyl)-L-tyrosine PET combined with MRI improves the diagnostic assessment of cerebral gliomas. Brain 128(Pt 3):678-87, 2005. PubMed

Weckesser M, Langen KJ, Rickert CH, Kloska S, Straeter R, Hamacher K, Kurlemann G, Wassmann H, Coenen HH, Schober O: O-(2-[¹⁸F]fluorethyl)-L-tyrosine PET in the clinical evaluation of primary brain tumours. Eur J Nucl Med Mol Imaging 32(4):422-9, 2005. PubMed

Pöpperl G, Götz C, Rachinger W, Gildehaus FJ, Tonn JC, Tatsch K: Value of O-(2-[¹⁸F]fluoroethyl)- L-tyrosine PET for the diagnosis of recurrent glioma. Eur J Nucl Med Mol Imaging31(11):1464-70, 2004. PubMed

Pauleit D, Floeth F, Tellmann L, Hamacher K, Hautzel H, Müller HW, Coenen HH, Langen KJ: Comparison of O-(2-18F-fluoroethyl)-L-tyrosine PET and 3-123I-iodo-alpha-methyl-L-tyrosine SPECT in brain tumors. J Nucl Med 45(3):374-81, 2004. PubMed

Spaeth N, Wyss MT, Weber B, Scheidegger S, Lutz A, Verwey J, Radovanovic I, Pahnke J, Wild D, Westera G, Weishaupt D, Hermann DM, Kaser-Hotz B, Aguzzi A, Buck A: Uptake of 18F-fluorocholine, 18F-fluoroethyl-L-tyrosine, and 18F-FDG in acute cerebral radiation injury in the rat: implications for separation of radiation necrosis from tumor recurrence. J Nucl Med 45(11):1931-8, 2004.PubMed

Pauleit D, Floeth F, Herzog H, Hamacher K, Tellmann L, Müller HW, Coenen HH, Langen KJ: Whole-body distribution and dosimetry of O-(2-[¹⁸F]fluoroethyl)-L-tyrosine. Eur J Nucl Med Mol Imaging30(4):519-24, 2003. PubMed

Kaim AH, Weber B, Kurrer MO, Westera G, Schweitzer A, Gottschalk J, von Schulthess GK, Buck A: (18)F-FDG and (18)F-FET uptake in experimental soft tissue infection. Eur J Nucl Med Mol Imaging 29(5):648-54, 2002. PubMed

Laverman P, Boerman OC, Corstens FH, Oyen WJ: Fluorinated amino acids for tumour imaging with positron emission tomography. Eur J Nucl Med Mol Imaging 29(5):681-90, 2002. PubMed

Jager PL, Vaalburg W, Pruim J, de Vries EG, Langen KJ, Piers DA: Radiolabeled amino acids: basic aspects and clinical applications in oncology. J Nucl Med 42(3):432-45, 2001. Review. PubMed

Weber WA, Wester HJ, Grosu AL, Herz M, Dzewas B, Feldmann HJ, Molls M, Stöcklin G, Schwaiger M: O-(2-[¹⁸F]fluoroethyl)-L-tyrosine and L-[methyl-11C]methionine uptake in brain tumours: initial results of a comparative study. Eur J Nucl Med 27(5):542-9, 2000. PubMed

Wester HJ, Herz M, Weber W, Heiss P, Senekowitsch-Schmidtke R, Schwaiger M, Stöcklin G: Synthesis and radiopharmacology of O-(2-[¹⁸F]fluoroethyl)-L-tyrosine for tumor imaging. J Nucl Med40(1):205-12, 1999. PubMed

[¹⁸F]FMISO

Author of the review: This email address is being protected from spambots. You need JavaScript enabled to view it.

Fluorine-18-labelled misonidazole, 2-nitro-3-(1-18fluoro-2-hydroxypropan-3-yl)imidazole, better known by the abbreviation [¹⁸F]FMISO, is currently the most widely used radioactive tracer for studying tumour hypoxia by positron emission tomography (PET). Hypoxia is defined as a reduced intracellular oxygen pressure, caused either by a reduced supply of, or an increased demand for, oxygen. The partial pressure of oxygen in normally oxygenated tissue commonly exceeds 40 mm Hg.

Hypoxia has been demonstrated in many disease states before, using various invasive methods such as immunohistochemistry. It is clear that hypoxia is present in conditions such as stroke or ischaemia of the heart muscle, but tumour hypoxia in particular is an important indicator of prognosis and of the body's response to treatment. The distribution of [¹⁸F]FMISO in the body takes place independently of blood flow, which also satisfies one of the main requirements for this type of tracer. [¹⁸F]FMISO-PET thus offers a suitable and currently very widespread way of non-invasively determining tissue hypoxia.

Properties

[¹⁸F]FMISO contains the fluorine radionuclide ¹⁸F. Fluorine ¹⁸F decays by positron emission (β+) with a half-life of 109.7 minutes. For diagnostic imaging by positron emission tomography (PET), the most important are the emitted γ photons with an energy of 511 keV, formed by the interaction of the emitted positrons with electrons (so-called positron annihilation). PET diagnostics using [¹⁸F]FMISO is a very advantageous method for locating hypoxic tissue in almost the entire human body. Its main application is found particularly in tumours of the brain, head and neck. The degree of hypoxia correlates significantly with the aggressiveness of tumours and their resistance to subsequent chemotherapy and radiotherapy.

Pharmacokinetics

Pharmacodynamics

[¹⁸F]FMISO passes through the cell membrane, including the blood–brain barrier, by passive diffusion into the cytoplasm, where it is immediately reduced by intracellular nitroreductases. In cells with a reduced partial pressure of oxygen, covalent binding to cellular molecules occurs at a rate that is inversely proportional to the intracellular oxygen concentration. The resulting nitro radical accepts a further electron to form an intermediate (R-NO). The intermediate is then further reduced to a strong alkylating agent (R-NH2), which subsequently reacts with macromolecules such as DNA, RNA and proteins. In cells with sufficient oxygen, the product is rapidly re-oxidised and the metabolites do not accumulate in the cell. Because accumulation of [¹⁸F]FMISO occurs only in cells with active nitroreductases, it is retained only in living hypoxic cells, but not in necrotic cells.

Pharmacokinetics

Fluoromisonidazole is a small molecule with a molecular weight of around 190 Da. The partition coefficient in the octanol/water system for [¹⁸F]FMISO is around 0.41. This corresponds to its lipophilicity and also to its ability to diffuse freely and distribute homogeneously throughout the body as early as 1 hour after administration, independently of blood flow. The distribution kinetics of 2-nitroimidazoles generally correspond to a linear two-compartment open model.

Quantification of the presence of [¹⁸F]FMISO by the tumour/plasma ratio is optimally performed 2 hours after administration, when the values of [¹⁸F]FMISO in normal tissue are already balanced with those in plasma and hypoxic tissues continue to selectively retain [¹⁸F]FMISO.

The usual route of elimination of [¹⁸F]FMISO is renal. A small fraction of [¹⁸F]FMISO is glucuronidated, which increases its water solubility, and it is then easily excreted by the kidneys into the urine as a conjugate. A small amount (<5%) is converted to aminoimidazole.

Toxicity

At present, the usual total administered dose of [¹⁸F]FMISO in a radiodiagnostic examination is less than 15 μg. Given the very small total dose administered and also the mechanism of action of [¹⁸F]FMISO, toxicity and pharmacokinetic interactions with other medicinal products appear very unlikely. On the basis of many studies performed, it can be stated that at the doses administered for radiodiagnostic purposes, the preparation has no toxic effects.

The only risk, as with all diagnostic radiopharmaceuticals, is the amount of administered radioactivity. Fluorine-18 is a high-energy emitter (511 keV); on the other hand, its very short physical half-life (110 minutes) significantly reduces the duration of the radiation burden on the target tissues. When 3.7 MBq/kg is administered, the whole-body dose for a man (70 kg) is 0.013 mGy/MBq and for a woman (57 kg) 0.016 mGy/MBq. The effective dose equivalent is 0.0134 mSv/MBq for a man (70 kg) and 0.0140 mSv/MBq for a woman (57 kg).

It can be summarised that the organ doses for [¹⁸F]FMISO are comparable with other commonly used nuclear medicine examinations, and the potential radiation risk associated with [¹⁸F]FMISO PET studies is within generally accepted limits.

Use

[¹⁸F]FMISO is a robust radiopharmaceutical used to obtain images for determining the extent of hypoxia using PET imaging. Imaging of hypoxia in various types of tumour growth has already been the subject of a whole series of scientific publications. For clinical applications, [¹⁸F]FMISO has been used for over 10 years in a number of countries in Europe, the USA and Australia, and it is currently the most widely used preparation for determining the degree of hypoxia in both oncological and non-oncological indications.

Oncological applications

The main use of [¹⁸F]FMISO is in administration to oncology patients. It has been shown that the presence of hypoxia is significantly associated with resistance to chemotherapy and radiotherapy and accelerates tumour progression. There is growing evidence that hypoxia-mediated aggressive tumour behaviour and resistance to therapy is brought about via the heterodimeric transcription factor HIF-1 (hypoxia inducible factor-1) through molecular processes that allow tumour cells to adapt to hypoxia, such as unregulated glycolysis, angiogenesis and p53 mutations. HIF-1 activates the transcription of genes whose protein products play a role either in increasing oxygen availability or in enabling metabolic adaptation to a hypoxic environment. The HIF-1 protein is overexpressed in a wide range of tumours and in their metastases. Benign non-invasive tumours mostly do not express HIF-1 at all. Strong expression of HIF-1 has been observed in glioblastomas and haemangioblastomas, which are among the most malignant and highly vascularised tumours of the nervous system. There is also a significant correlation between HIF-1 expression and apoptotic and pro-apoptotic factors.

Both in vitro and in vivo studies show that hypoxia can significantly alter cell behaviour, e.g. by expansion of cells with a low apoptotic index and an increasing rate of cell mutations. Hypoxia causes an increase in the expression of genes related to tumour cell survival (e.g. VEGF (vascular endothelial growth factor), glycolytic enzymes, signalling molecules) and also cell adaptation to a hypoxic environment (inhibition of apoptosis and cell differentiation, increased angiogenesis). These adaptive changes in the genome and proteome of tumour cells result in a much more aggressive phenotype of these cells.

It has been shown that, compared with normal cells, hypoxic cells are several times more resistant to ionising radiation, which subsequently leads to resistance to radiotherapy. In hypoxic tissue, it is necessary to irradiate with a dose 2.5 to 3.5 times higher than in normoxic tissue for the same radiotherapeutic effect. Knowledge of the degree of hypoxia in a tumour helps in choosing the right strategy in the treatment of a tumour disease.

It is precisely the growing need to detect the degree of hypoxia as a prognostic marker that has led to efforts to determine the extent of hypoxia as objectively as possible. The gold standard for determining the amount of oxygen used to be the invasive method using an oxygen electrode. At present, the most widespread and most studied non-invasive method of determining hypoxia is precisely the combination of the [¹⁸F]FMISO radiotracer with PET imaging.

Although [¹⁸F]FMISO can generally be used to determine hypoxia in a whole range of tumours, its most common use is in tumours of the central nervous system (meningiomas and highly malignant gliomas) and malignant tumours of the head and neck.

Non-oncological applications

The use of [¹⁸F]FMISO for non-oncological determination of hypoxia is primarily focused on brain hypoxia, and subsequently on myocardial hypoxia. The most commonly studied cases are monitoring the extent of hypoxia in ischaemia of brain tissue and acute stroke, as well as myocardial ischaemia and the extent of tissue damage after myocardial infarction. There are also studies dealing with the detection of anaerobic infection of the body using [¹⁸F]FMISO.

Conclusion

Determining the degree of hypoxia using [¹⁸F]FMISO-PET is an easy procedure that is very well tolerated by patients. The imaging itself takes 20–30 min and begins 75–150 min after administration of the radiopharmaceutical. Well-contrasted images can be obtained using a medium radiation dose, commonly around 250 MBq, similar to a skeletal examination.

References

Bentzen S.M., Gregoire V.: Molecular imaging-based dose painting: a novel paradigm for radiation therapy prescription. Semin Radiat Oncol. 2011, 21(2):101-10. PubMed

Mönnich D. et al.: Modelling and simulation of [(18)F]fluoromisonidazole dynamics based on histology-derived microvessel maps. Phys Med Biol. 2011, 7;56(7):2045-57. PubMed

Choi W. et al: Planning study for available dose of hypoxic tumor volume using fluorine-18- labeled fluoromisonidazole positron emission tomography for treatment of the head and neck cancer. Radiother Oncol. 2010, 97(2):176-82. PubMed

Mees G. et al: Molecular imaging of hypoxia with radiolabelled agents. Eur J Nucl Med Mol Imaging. 2009, 36(10):1674-86. PubMed

Krohn K.A. et al.: Molecular Imaging of Hypoxia. J. Nucl. Med. 2008, 49, 129S-148S. PubMed

Lee S.T., Scott A.M.: Hypoxia Positron Emission Tomography Imaging With 18F- Fluoromisonidazole. Semin. Nucl. Med. 2007, 37, 451-461. PubMed

Padhani A.R. et al.: Imaging oxygenation of human tumours. Eur Radiol 2007, 17: 861–872. PubMed

Padhani A.: PET imaging of tumour hypoxia. Cancer Imaging 2006, 6, S117-S121. PubMed

Bruehelmeier M. et al.: Assessment of Hypoxia and Perfusion in Human Brain Tumors Using PET with 18F-Fluoromisonidazole and 15O-H2O. J. Nucl Med. 2004; 45:1851–1859. PubMed

Graham M.M. et al.: Fluorine-18-Fluoromisonidazole Radiation Dosimetry in Imaging Studies. J. Nucl. Med. 1997, 38, 1631-1636. PubMed

[¹²³I]NaI

[¹²³I]sodium iodide, [¹²³I]NaI

Author of the review: Ing. Ondřej Lebeda, Ph.D.

[¹²³I]sodium iodide is a very good diagnostic agent in functional and morphological studies of the thyroid gland, using scintigraphy of the uptake test. Compared with [99mTc]sodium pertechnetate, which can be used for the same purpose, the quality and sensitivity of thyroid imaging with [¹²³I]sodium iodide are significantly higher. It is an ideal diagnostic agent when planning ¹³¹I therapy of thyroid carcinoma. To date, a smaller amount of [¹³¹I]sodium iodide is often used for these purposes; however, it causes a radiation burden on the thyroid more than 2 orders of magnitude higher, and thus demonstrably reduces the uptake of the therapeutic dose of ¹³¹I.

Properties

The diagnostic radiopharmaceutical [¹²³I]sodium iodide is essentially an aqueous solution of a non-weighable quantity of sodium iodide which, instead of the stable isotope of iodine, contains its radioisotope ¹²³I. This radioisotope has a half-life of 13.27 h. Unlike the commonly used ¹³¹I (half-life 8.01 d), during its transformation it emits no particulate radiation, only gamma radiation of an energy ideal for imaging on SPECT cameras (159 keV). The radiation burden on the body is therefore more than 2 orders of magnitude lower per unit of administered activity compared with ¹³¹I (only 23 mSv/MBq at 55 % accumulation in the thyroid gland). Moreover, thanks to the optimal energy of the emitted gamma radiation, activities approximately 4× lower than in the case of ¹³¹I are sufficient for good-quality thyroid imaging. The overall radiation burden on the body is thus roughly 500× lower compared with ¹³¹I.

Because iodine is deposited in the thyroid gland very rapidly and selectively, even in the case of oral intake, [¹²³I]sodium iodide is an exceptionally suitable radiopharmaceutical for thyroid imaging, both in terms of the quality of the imaging itself and because of the very low radiation burden on the patient.

Pharmacokinetics

After oral administration, absorption of iodide is essentially complete within 1–2 hours, but it may be slowed by food present in the stomach.

Distribution after the drug enters the systemic circulation leads to dominant accumulation of iodide in the thyroid gland, with a maximum 24–48 hours after administration. As early as 5 hours after ingestion, 50 % of the maximum concentration in the thyroid gland is reached. These ratios may be affected by factors such as age, thyroid status, or the degree of renal iodide clearance. Accumulation may be further affected by concomitant medication.

The biological half-life of iodide removal from the thyroid gland has been estimated at 80 days (adult), and at 65, 50, 40 and 30 days for children aged 15, 10, 5 and 1 year respectively. The time window for diagnostic administration of ¹²³I iodide is therefore governed by the physical half-life (13.27 h).

From all other organs, iodide is removed with a half-life of renal clearance, which is about 8 hours. Iodide is eliminated from the body 90 % in the urine, the remainder in the faeces and sweat. Within 24 hours, about 50 % of the iodide not bound in the thyroid gland is excreted in the urine.

A small amount of iodide is taken up by the salivary glands, the gastric mucosa, breast milk, the placenta and the choroid plexus. The thyroid gland removes almost 20 % of the iodide from the blood on the first pass. The accumulated iodine is incorporated in the thyroid gland into organic compounds from which thyroid hormones are formed. Iodine is also released intrathyroidally from iodinated amino acids not used in hormone synthesis. The iodine level in the thyroid gland is relatively high (10 mg) and has a slow turnover.

Toxicity

The acute toxicity of iodide was tested after oral administration of sodium iodide to rats and mice. The LD50 values found were 4340 mg/kg and 1000 mg/kg respectively. After intravenous administration, the LD50 value is 1060 mg/kg for rats and 760 mg/kg for dogs.

The safety factor is greater than 106, given the low administered quantity of the compound (< 0.1 µg for diagnosis). For the diagnostic administration of ¹²³I, no relevant toxic effects of very high doses of sodium iodide are known. No data are available from animal studies concerning toxicity after repeated administration or reproductive toxicity. No teratogenic or mutagenic effects are known.

Contraindications are also not known. A relative contraindication may be a disease accompanied by impaired absorption from the gastrointestinal tract, in which the absorbed dose from ionising radiation increases.

Use

[¹²³I]sodium iodide is a very good diagnostic agent in functional and morphological studies of the thyroid gland, using scintigraphy of the uptake test.

The recommended administered activity for adults (70 kg) ranges between 3.7 and 18 MBq. A lower activity (3.7 MBq) is recommended for use in the uptake test, a higher one (11.1–14.8 MBq) for scintigraphy. For the examination of patients after surgical removal of the thyroid gland, 14–18 MBq is administered. ¹²³I must be administered orally in solution. Imaging is performed 4–6 hours (16–24 hours) after administration. To calculate the degree of accumulation of ¹²³I in the thyroid gland, one of the reliable standard procedures must be used (usually those recommended by the manufacturer of the given gamma camera).

In small children, when calculating the administered activity for scintigraphy, the value A(adult) = 14.8 MBq must be used if the imaging is to be of sufficient quality.

Scientific literature

Neumann DR, Obuchowski NA, Difilippo FP: Preoperative 123I/99mTc-sestamibi subtraction SPECT and SPECT/CT in primary hyperparathyroidism. J Nucl Med, 2008. PubMed

Fugazzola L, Persani L, Vannucchi G, Carletto M, Mannavola D, Vigone MC, Cortinovis F, Beccaria L, Longari V, Weber G, Beck-Peccoz P: Thyroid scintigraphy and perchlorate test after recombinant human TSH: a new tool for the differential diagnosis of congenital hypothyroidism during infancy. Eur J Nucl Med Mol Imaging34(9):1498-503, 2007. PubMed

Schoen EJ, Clapp W, To TT, Fireman BH: The key role of newborn thyroid scintigraphy with isotopic iodide (123I) in defining and managing congenital hypothyroidism. Pediatrics 114(6):e683-8, 2004. PubMed

Hilditch TE, Dempsey MF, Bolster AA, McMenemin RM, Reed NS: Self-stunning in thyroid ablation: evidence from comparative studies of diagnostic 131I and 123I. Eur J Nucl Med Mol Imaging 29(6):783-8, 2002. PubMed

LaFranchi S: Congenital hypothyroidism: etiologies, diagnosis, and management. Thyroid 9(7):735-40, 1999. Review. PubMed

Morita S, Umezaki N, Ishibashi M, Kawamura S, Inada C, Hayabuchi N: Determining the breast-feeding interruption schedule after administration of 123I-iodide. Ann Nucl Med 12(5):303-6, 1998. PubMed

Radionuclide generator ⁸¹Rb/⁸¹mKr

[¹²³I]sodium iodide, [¹²³I]NaI

Author of the review: Ing. Helena Švecová, Ph.D.

Radioactive gases have been used successfully for lung ventilation examinations since the 1950s. First, in 1953, Knipping et al. used a gas mixture with ₁₃₁I, and two years later the same group introduced ₁₃₃XeXe (half-life 5.27 h) into lung diagnostics. The greatest interest in ₁₃₃XeXe arose in the 1960s, when a number of studies of lung diseases were carried out with this gas. As a result, ₁₃₃XeXe became a routinely used tool for lung examinations.

In 1968, Yano and Anger outlined the possibility of using _81mKr for lung examinations. ₈₁mKr has a half-life of only 13.1 seconds, but it can be obtained continuously from its parent nuclide ₈₁Rb (4.576 h) in a radionuclide generator. The short half-life of _81mKr is, surprisingly, one of its advantages, because it significantly reduces the radiation burden on both the patient during the examination and the staff, and practically no radioactive waste is produced. Another advantage of _81mKr is the energy of the emitted γ radiation, 190 keV, which, in terms of resolution, is more favourable for SPECT cameras than the energy of the main γ line emitted by ₁₃₃Xe (81 keV).

For many reasons, ₈₁mKr is a very suitable radionuclide for lung ventilation examinations in cases of suspected pulmonary embolism, obstructive lung disease, pulmonary emphysema and other lung diseases.

Properties

The generator contains ₈₁Rb (half-life 4.576 h) in equilibrium with the daughter radionuclide _81mKr (half-life 13.1 s), which emits γ radiation of energy 190.4 keV. In a mixture with air it is used for lung ventilation examinations.

Pharmacokinetics

Krypton is a noble gas that is completely chemically inert and, in the lungs, practically does not pass into the blood. When 81mKr is used for a lung examination, the mixture of krypton and air is inhaled and exhaled again in unchanged form. Given the physical half-life of _81mKr (13.1 s), it is not possible to determine the biological half-life or to study other pharmacokinetic data.

The pharmacodynamic effects of the medicinal product are also not manifested, because the amount of the agent taken in by inhalation is low and, given the half-life of the _81mKr nuclide (13.1 s) and the administered activity, the absorbed quantity of gas is negligible, as are any possible manifestations of interaction of the gas with the body.

Toxicity

The amount of radiopharmaceutical taken in by inhalation is far below the amount of krypton that we take in naturally by breathing air (on the order of 10,000× more). Considering the chemical toxicity of _81mKr is therefore irrelevant. The radiotoxicity of _81mKr is significantly lower than that of other radiopharmaceuticals, given its very short half-life and the absence of particulate radiation. The effective dose in an adult (70 kg) is 2.7×10-5 mSv/MBq, and in a routine examination it is in the range of tenths of a mSv. The equivalent dose in the lungs is between 60 and 140 μGy. The radiation burden of an examination using _81mKr is significantly lower than that of other commonly used nuclear medicine examinations.

Use

Conclusion

The use of _81mKr for lung ventilation examinations makes it possible to study a range of diseases. Compared with ₁₃₃XeXe, scintigraphy with _81mKr has better resolution, the patient and staff are exposed to a lower radiation burden, active cooperation of the patient is not required for the examination, and, in addition, the use of _81mKr allows several projections to be performed in quick succession. Given the half-life of the parent radionuclide (4.576 h), the ⁸¹Rb/⁸¹mKr radionuclide generator can also be distributed to relatively distant facilities, but on the other hand this half-life is so short that practically no radioactive waste is produced.

The ⁸¹Rb/⁸¹mKr radionuclide generator is used mainly for lung ventilation examinations in pulmonary embolism and COPD, and further for a number of other diseases of the respiratory tract.

References

Radioactive gases have been used successfully for lung ventilation examinations since the 1950s. First, in 1953, Knipping et al. used a gas mixture with 131I, and two years later the same group introduced ₁₃₃XeXe (half-life 5.27 h) into lung diagnostics. The greatest interest in ₁₃₃XeXe arose in the 1960s, when a number of studies of lung diseases were carried out with this gas. As a result, ₁₃₃XeXe became a routinely used tool for lung examinations.

In 1968, Yano and Anger outlined the possibility of using _81mKr for lung examinations. _81mKr has a half-life of only 13.1 seconds, but it can be obtained continuously from its parent nuclide ₈₁Rb (4.576 h) in a radionuclide generator. The short half-life of _81mKr is, surprisingly, one of its advantages, because it significantly reduces the radiation burden on both the patient during the examination and the staff, and practically no radioactive waste is produced. Another advantage of _81mKr is the energy of the emitted γ radiation, 190 keV, which, in terms of resolution, is more favourable for SPECT cameras than the energy of the main γ line emitted by ₁₃₃XeXe (81 keV).

_81mKr is, for many reasons, a very suitable radionuclide for lung ventilation examinations in cases of suspected pulmonary embolism, obstructive lung disease, pulmonary emphysema and other lung diseases.

Institutions:

State Institute for Drug Control

Czech Society of Nuclear Medicine

Ministry of Health of the Czech Republic

International Atomic Energy Agency

MedDRA MSSO

State Office for Nuclear Safety

Czech Medical Chamber

Czech Chamber of Pharmacists

European Association of Nuclear Medicine

EudraVigilance