CS 
18F-sodium fluoride
Author of the review:
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
