Radiotracers and radiopharmaceuticals are substances that follow the behaviour of various biological processes. They are also used for flow visualisation through different medical imaging modalities such as Positron Emission Tomography (PET imaging), Single Photon Emission Computed Tomography (SPECT imaging) and Computed Radioactive Particle Tracking (CARPT) systems.
Radiolabelled drug molecules
Radiopharmaceuticals – are used in vitro and in vivo to study drug metabolism profiles. The premise behind radiolabelled drugs is to quantify the amount of drug-related substances in different biological systems. The advantage of radiolabelled isotopes is the ability to apply chromatographic separation and quantify the individual metabolites.
Therefore, radiolabelled drugs are used mostly in ADME (absorption, distribution, metabolism and excretion) studies. Carbon-14 (14C) labelled compounds benefit these investigations because of the higher metabolic stability of this compared to the tritium (3H) tagged version. The radiolabel is inserted into the metabolically stable core group of the compound. The radiolabel may be placed both on stable and labile moieties depending on the labelling requirements. Furthermore, double-labelled compounds with different isotopes, for example, 13C/14C or 3H/14C might be synthesised to aid in metabolite identification and quantification of the individual moieties.
Radiotracers used in the investigation of metabolic pathways fall into two categories:
- Radioisotopes of the parent compound, for example, 11C-palmitate and 11C-glucose follow the same metabolic fate of the parent compound to give a quantitative evaluation of the metabolic pathway.
- The analogues of the parent compound such as [2-18F]-2-fluoro-2-deoxyglucose [FDG] and [123I]-BMIPP (β-methyl-iodophenyl-pentadecanoic acid) provide qualitative assessments of metabolism because they are generally retained by the tissue and make imaging more viable.
The [1-11C]glucose cannot be biochemically indistinguishable from glucose and therefore can follow the exact fate of glucose during the metabolism. This process releases cardiomyocytes as 11CO2 and results in uptake, retention and disappearance of the radiotracer from the heart.
In the other situation, FDG is taken up and phosphorylated by hexokinase and does not undergo further metabolism in the cardiomyocyte because of the modification of the carbohydrate structure from glucose to deoxyglucose.
As a result, FDG becomes trapped in the cell. Kinetic analysis of the time-activity curves for FDG can be used to estimate the initial uptake and phosphorylation of glucose. This process provides no information regarding the oxidative fate of glucose, and kinetic analysis demonstrates irreversible trapping compared to the accumulation and disappearance of other radiotracers.
The irreversible ‘trapped’ radiotracers regarding myocardial substrate utilisation generate:
- Information regarding a part of a given metabolic process;
- differences in the structure of the parent compound and the radiotracer will alter the reliability with which the tracer measures the utilisation of the parent compound;
- the relationship between tracer and detection can vary under different metabolic conditions.
Module and laboratory radiotracers
Radiotracers can be classified as to whether they are single photon-emitting or positron-emitting nuclides. PET radiotracers require the coincidence detection of the two 511-keV photons produced by positron annihilation combined with the attenuation correction that is needed for the radiopharmaceutical. Also, kinetic analysis can be performed with the positron-emitting metabolic radiotracers to generate quantitative measurements of rates of substrate uptake and metabolism.
However, single photon-emitting metabolic radiotracers can only provide qualitative assessments of metabolic processes. The primary advantage of these radiotracers is that an on-site cyclotron is not required to produce the short-lived carbon-11 and oxygen-15 radiopharmaceuticals. This is a significant advantage and is accelerating the newer technetium-99m (Tc-99m) labelled fatty acid analogues for metabolic imaging by building on the established platform of iodine-123 tagged fatty acid analogue namely, BMIPP.
Research into radiolabelled nanoparticles offers several advantages such as prolonged circulation time, high plasma stability and a high potential for clinical applications in the early diagnosis of cancer and cardiovascular diseases.
This theranostic technology is able to generate single-photon emission computed tomography (SPECT) or positron emission tomography (PET) for targeted in vivo imaging. Both these technologies are highly sensitive, specific and useful inaccurate quantification compared to in vivo imaging techniques that have limited application due to the type of tissue involved.
Radiolabelled monoclonal antibodies (Mab) – are being developed to target specific antigens – have been safely administered to patients with leukaemia. For example, yttrium-90-anti-CD25 was shown to be active against acute T-cell leukaemia. Also, iodine-131-anti-CD33 was active in the treatment of acute myeloid leukaemia (AML), Myelodysplastic syndrome (MDS) including myeloblastic chronic myeloid/myelogenous leukaemia (CML]). Other indications involving yttrium-90-anti-CD33 and, iodine-131-anti-CD45 were effective against AML, ALL (Acute lymphoblastic leukaemia) and MDS. The radiolabelled Mab, rhenium-188-anti-CD66c showed promise against AML, ALL and CML.
Radioconjugates that emit alpha particles, for example, bismuth-213-anti-CD33 and actinium-225-anti-CD33 may be better suited for the treatment of small-volume disease.
In the 1980s, Tc-99m–labelled hepatobiliary based radiopharmaceuticals became available for ‘experimental’ treatment plans, due to the production of superior images. These imaging agents superseded iodine-123 rose bengal and gave rise to three U.S. Food and Drug Administration (FDA) approved hepatobiliary radiopharmaceuticals for clinical use. This included the first Tc-99m dimethyl iminodiacetic acid (IDA) and has become a generic term for all Tc-99m IDA radiopharmaceuticals. Tc-99m contains the ability to bridge between two IDA ligand molecules and binds to an acetanilide analogue of lidocaine. The whole structure determines the overall radio-pharmacokinetic profile including modifications to the phenyl ring moiety resulting in the different pharmacokinetics of IDA radiopharmaceuticals.
Several radiopharmaceuticals such as Tc-99m-hepatobiliary (HIDA) analogues that possess different chemical substituents on the aromatic ring have been investigated. This demonstrated to have less uptake including slower clearance than the approved commercially available agents. In another example, Tc-99m-sestamibi is coordinated to six methoxyisobutylisonitrile (MIBI) ligands. The resultant complex is a cationic SPECT imaging agent that accumulates in cytoplasm and mitochondria by the process of passive diffusion across the polarised cellular/organelle membrane.
Similarly, for thallium-201, Tc-99m-sestamibi is generally excluded from the brain via the blood-brain barrier (BBB), and therefore tumour uptake appears to be mainly related to BBB breakdown. The normal MIBI distribution is in the pituitary gland, scalp and choroid plexus. However, the MIBI radiotracer is not imageable in normal brain parenchyma. Also, normal uptake of MIBI in the choroids can be perplexing and limit the evaluation of deep periventricular tumours.
However, the research using Tc-99m-sestamibi SPECT imaging of glioma recurrence following radiation therapy demonstrated a pooled sensitivity of 90% and specificity of 92%.
Nevertheless, Tc-99m-sestamibi has better imaging properties than thallium-201 producing an energy of140 KeV and higher allowable injection dosages of up to 30 mCi. However, further research is required to evaluate the benefits of Tc-99m-sestamibi for diagnosis and prognosis including the detection of tumour recurrence over the superiority of thallium-201. Interestingly, studies have suggested that Tc-99m-sestamibi has increased specificity over thallium-201.
Further, investigations using Tc-99m-sestamibi as a prognostic biomarker for patient survival, and a predictive biomarker in chemotherapy treatment is promising. Research has shown that quantitative analysis of Tc-99m-sestamibi uptake using SPECT imaging correlates well with survival time in patients following chemoradiotherapy. This modern approach contributes to the overall prognosis in the patient by evaluating the chemotherapy response of Tc-99m-sestamibi.
Overall, the collective evidence points towards Tc-99m-sestamibi to be an early indicator of treatment success by demonstrating tumour progression on average four months before changes detected on magnetic resonance imaging. Remarkably, Tc-99m-sestamibi is eliminated from cells by P-glycoprotein, which also acts as an energy-driven efflux pump for several antineoplastic agents. Moreover, multiple drug resistance (MDR)-1 gene expression as demonstrated by Tc-99m-sestamibi does not appear to correlate with chemoresistance in gliomas.
Technetium-99m-tetrofosmin known as Myoview was approved by the FDA in 1996 and in some respects is similar to Tc-99m-sestamibi. Myoview is rapidly removed from the liver compared to other Tc-99m imaging-based agents. The tetrofosmin ligand is a member of the diphosphine chemical class (6,9-bis [2-ethoxyethyl]-3,12-dioxa-6,9-diphosphatetradecane). This SPECT imaging agent is prepared from a commercial kit (Myoview) and is similar to Tc-99m-sestamibi. This Tc-99m-tetrofosmin is a lipophilic cation that localises near mitochondria in the myocardial cell and remains fixed at that site.
Immediately after intravenous injection, the Tc-99m tetrofosmin is rapidly cleared from the bloodstream and the myocardial quickly uptakes the radiotracer. However, the first-pass extraction is less than that of sestamibi (50% vs 60%) including 1.2% of the administered dose taken up in the myocardium within 5 minutes after injection. The extraction is proportional to blood flow but underestimated at high flow rates. Furthermore, the heart-to-lung and heart-to-liver ratios improve over time because of physiological clearance through the liver and kidneys.
Studies have found that the heart-to-liver rates are higher for Tc-99m tetrofosmin compared to sestamibi. This is because of faster hepatic clearance which allows for further imaging. However, after the stress exercise, an imaging interval of 15 minutes is achievable followed by rest studies that started 30 minutes after the injection.
The dosimetry profile is comparable to that of Tc-99m sestamibi and the gallbladder is capable of receiving a high dose rate at 5.4 rems/20 mCi, compared to the colon for sestamibi. The reason for the difference may be due to whether the studied subjects ate and had gallbladder contraction. The whole-body radiation effective dose is 0.8 rem/30 mCi.
Nuclear medicine healthcare involves the use of specific radiotracer laboratories for the administration of radiopharmaceuticals to patients including therapeutic procedures. Therefore, for medical imaging, the radiation emitted from these radiopharmaceuticals must be detected by external detectors to determine its in vivo distribution in the human body. Furthermore, the emitted radiation must be absorbed by targeted tissues for radiopharmaceutical medicine to achieve the desired effect of killing cancer cells. Therefore, theranostics requires an understanding of the type of radioactivity, the amount administered, including the radiation emissions and how it interacts with the surrounding healthy tissue in the human body to personalise a treatment plan.
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