Figure 2. [68GA]-DOTA

Intracellular signalling pathways in neuroendocrine tumours showing the PI3k/AKT/mTOR; RAS/RAF/MEK/ERK; PLC/PKC and JAK/STAT pathways.

The Ras-ERK (extracellular signal-regulated kinase) and PI3K (phosphatidylinositol 3-kinase)-mTOR (mammalian target of rapamycin) signaling pathways are the cell's chief mechanisms for controlling cell survival, differentiation, proliferation, metabolism, and motility in response to extracellular cues. Components of these pathways were among the first to be discovered when scientists began cloning proto-oncogenes and purifying cellular kinase activities.

SSR: somatostatin receptor
PI3K: phosphoinositide 3-kinase
RAS: rat sarcoma protein
PLC: phospholipase C
PKC: protein kinase C
JAK/STAT: Janus kinase signal transducer and activator of transcription.

- Mendoza M. The Ras-ERK and PI3K-mTOR Pathways: Cross-talk and Compensation; Trends Biochem Sci. 2011 June ; 36(6): 320–328

Figure 3. [18F]-SODIUM FLUORIDE

Fluoride-18 sodium fluoride (18F-NaF) was the first widely used radiopharmaceutical for skeletal scintigraphy, it was introduced in 1962 and approved by theFDA in 197 for clinical use.
Pharmacokinetics:
18F-NaF has negligible plasma protein binding, rapid blood and renal clearance, and high bone uptake, which allows whole-body imaging as early as 45–60 min after its venous injection.
The rate-limiting step of 18-NaF bone uptake is blood flow.
Around 30% of the injected dose is sequestered within erythrocytes; however, this fact does not affect the bone uptake  because it freely diffuses across membranes, and almost all the radiopharmaceutical delivered  is retained by the bone after a single pass of blood.
18F-NaF is rapidly cleared from plasma, only 10% remains one hour after the injection, depending on the urine flow rate.
18F-NaF uptake and retention depends on the exposed area of the bone’s surface, which is larger in a variety of benign and malignant bone disorders.
The relationship between osteoblastic and osteoclastic activities determine the incorporation of 18F-NaF into the bone matrix, an increase in the osteoblastic activity increases the 18F-NaF uptake.
For bone deposition, 18F-ions need to pass from plasma through the extracellular space into the shell of bound water surrounding each hydroxyapatite crystal, After chemisorption onto hydroxyapatite, 18F rapidly exchanges for an  OH-  ion on the surface of the hydroxyapatite matrix to form fluoroapatite and migrates into the crystalline matrix of the bone, where is retained until the bone gets remodeled.

- Blau M, Nagler W, Bender M. Fluorine 18: a new isotope for bone scanning. Journal of nuclear medicine: official publication, Society of Nuclear Medicine; 1962 (3):332-4
- Carlson C, Armstrong W, Singer L. Distribution, migration and binding of whole fluoride evaluated with radiofluoride. Am K Physiol. 1960; 199:187-9
- Blake GM, Park Holohan SJ, Caok GJ, Fogelman L. Quantitative studies of bone with the use of 18F-Fluoride and Tc methylene diphosphonate. Seminars in nuclear medicine. 2001; Jan:31(1):28-49.
- Hawkins RA, et al: Evaluation of the Skeletal Kinetics of Fluorine 18-Fluoride Ion with PET; JNuclMed 1992;33:633-642
- Czernin J, et el. Molecular Mechanisms of Bone 18F-NaF Deposition; J Nucl Med. 2010 December ; 51(12): 1826–1829

Figure 4. [18F]-FLUOROTHYMIDINE

The synthesis of 11C and 18F-thymidine and the development of PET instrumentation led to the ability to image thymidine uptake and measure cell growth noninvasively. 18F-FLT is  a valuable marker of tumor response to antiproliferative treatments including RT.

DNA synthesis is required for cell growth and proliferation, nucleotides of the four bases (cytosine, guanine, adenine, and thymidine) are required for this task, and measurements of the rate of their incorporation into DNA yield the DNA synthetic rate.

Of the four nucleosides, thymidine is the only one incorporated exclusively into DNA and provides a measure of DNA synthesis independent of RNA synthesis, therefore, thymidine incorporation into DNA is considered a gold standard measure of proliferation.

PET- CT with [11C]-thymidine represents the standard for imaging proliferation, because it is identical to native thymidine, eliminating potential differences in uptake caused by differences in metabolism between thymidine and its analogues.

Thymidine outside the cell can be incorporated into DNA by the exogenous pathway:
 Flux through this pathway is ultimately controlled by the rate of DNA synthesis and is controlled by thymidine kinase.
T-MP: thymidine monophosphate
T-DP: thymidine diphosphate
T-TP: thymidine triphosphate


- Everitt J, Ball DL, et al. Differential 18F-FDG and 18F-FLT Uptake on Serial PET/CT Imaging Before and During Definitive Chemoradiation for Non–Small Cell Lung Cancer; J Nucl Med 2014; 55:1069–1074
- D.A. Mankoff et al / Radiol Clin N Am 43 (2005) 153–167
- J Pharm Pharmaceut Sci (www. cspsCanada.org): 10(2) 180-202, 2007
- Mercer R. Molecular imaging agents for clinical positron emission tomography in oncology other than fluorodeoxy- glucose (FDG): applications, limitations and potential; - J Pharm Pharmaceut Sci: 10(2) 180-202, 2007

Figure 5. [11C] and [18C]-CHOLINE

Radiolabeled choline (11 C-choline) has been used to study tumor lipid metabolism.

Choline kinase (ChoK) is the first enzyme responsible for the de novo synthesis of phosphatidylcholine (PC), one of the basic lipid components of membranes. ChoK is responsible of the generation of phosphorylcholine (PCho) from its precursor, choline.  

Overexpression of Choline kinase is a frequent event in the development of human cancers. Choline kinase expression has been shown to be associated with certain cell stresses and has also been shown to act as a second messenger in cell growth signaling. Human cancer cells do not store significant amounts of triglycerides but esterify fatty acids to phospholipids, such as phophatidylcholine.

Pharmacokinetics:
The first step of choline accumulation by tumor cells is transport across the cell membrane by various transporters. Since choline is a polar molecule, uptake by passive diffusion is low.
ChoK phosphorylates free choline to phospho-choline (PCho), which represents the first step of choline metabolism. Catalyzed by choline-cytidyltransferase (CCT), PCho can then react with CTP (cytosine triphosphate) to form cytosine diphosphate-choline (CDP-choline). The phosphorylcholine unit of CDP-choline is then transferred to a diacylglycerol (DAG) by cholinephosphotransferase (CPT) to form phosphatidylcholine (PC), a major constituent of the mammalian cell membrane. Intracellular choline levels are determined by both the rate of choline uptake as well as the rate of phosphatidylcholine synthesis and degradation

Urinary excretion of 11 C-choline is markedly lower than that of 18 F-FDG, which facilitates evaluation of primary and recurrent tumors in the pelvis.

- Ramírez de Molina A,  et al. Overexpression of choline kinase is a frequent feature in human tumor-derived cell lines and in lung, prostate, and colorectal human cancers. Biochemical and Biophysical Research Communications 2002; 296:580–583
- Plathow C, Weber WA. Tumor Cell Metabolism Imaging; J Nucl Med; 2008;49:43S-63S.

Figure 6. [18F]-FES

Intracellular receptors are a separate category of imaging agents that must both target a relevant binding partner and cross the cell membrane. The estrogen receptor is an intracellular receptor that is used to diagnose and stage breast cancers. Several PET imaging agents have been developed preclinically to evaluate the expression of these nuclear intracellular receptors such as 18F-fluoroestradiol.

FES has binding characteristics similar to estradiol for both  the  Estrogen Receptors and  the  transport  protein,  SHBG (45% of 18F FES in circulating plasma is  bound  to  SHBG,  and  much  of  the  reminder  is  weakly bound to albumin)

Like other steroids, FES is highly extracted by the liver and, once injected is rapidly taken up and metabolized. As a result, early blood clearance  is  rapid,  reaching  a  plateau  20-30  minutes  after injection. By 20 minutes, only 20% of the circulating radio-activity is in the form of non-metabolized FES. Metabolite excretion into the urine, mostly in the form of the glucuronide conjungates, occurs at a rate comparable with release from the liver.

There is a pattern of enterohepatic circulation, where metabolites excreted into the bile are efficiently reabsorbed  in  the  small  intestine,  with  little  radioactivity reaching the large intestine.  Because early FES clearance is rapidand metabolite background is nearly constant, imaging starting at 30 minutes after injection can provide good visualization  of  estrogen  containing  tissues,  even  in  sites  close  to blood pool structures.

Estrogen receptor kinetics: Estrogen must exist in the free form separated from its carrier protein (sex-steroid-binding globulin [SBG]) prior to diffusion intro the cell.
The strogen receptor undergoes a temperature-dependent conformational change to the 5.4S form prior to nuclear transport.
After interacting with the euchromatin, the receptor complex is probably recirculated.


- Burdette J. In vivoimaging of molecular targets and their function inendocrinology; Journal of Molecular Endocrinology(2008)40,253–261
- Moresco RM, et al. Systemic and Cerebral Kinetics of 16a [18F]Fluoro-17b-estradiol: a ligand for the in vivo assessment of estrogen receptor binding parameters. Cereb Blood Flow Metab, 1995; 15 (2):301-311.
- Sundararajan L, et al. 18F-Fluoroestradiol; Semin Nucl Med;2007; 37:470-476

Figure 7. [18F]-DTBZ

Imaging the type 2 vesicular monoamine transporter (VMAT) in the brain provides a measurement reflecting the integrity of all three monoaminergic neurons

VMAT2 is a relatively unspecific transporter, as it functions to move a wide variety of amines into the vesicle lumen, including dopamine, serotonin, norepinephrine, histamine, and a number of structurally related molecules.

Dopamine is a simple organic chemical that functions as a neurotransmitter in the brain. As part of the reward pathway, dopamine is manufactured in nerve cell bodies located within the ventral tegmental area and is released in the nucleus accumbens and the prefrontal cortex. The motor functions of dopamine are linked to a separate pathway, with cell bodies in the substantia nigra that manufacture and release dopa-mine into the striatum. Dopamine is transported to the synaptic sites and packaged into vesicles for release, which occurs during synaptic transmission. Following release of dopamine into the synapse, dopamine interacts with postsynaptic dopamine recep-tor sites. Free dopamine in the synapse is also reabsorbed into the presynaptic terminal via dopamine transporter.

α[11C]Dihydrotetrabenazine (DTBZ) is a stable, stereoselective tracer which binds selectively to VMAT 2 and is less regulated by intrasynaptic dopamine than are other dopaminergic tracers. 18F-DTBZ, gives the highest specific signal in the assessment of presynaptic neuronal degeneration.

- Sabba L. Imaging in Neurodegenerative Disorders; Oxford University Press; first edition, 2015,  UK, pp: 164-167

Figure 8. [68GA]-PSMA

Prostate-specific membrane antigen (PSMA) is a promising new target for specific imaging of prostate cancer (Pca).

The prostate-specific membrane antigen (PSMA) is a type II integral membrane glycoprotein that was first detected on the human prostatic carcinoma.

In malignant tissue, PSMA has been suggested to be involved in angiogenesis, as increased PSMA expression was found to be expressed in the stroma adjacent to neovasculature of solid tumors. Due to its selective overexpression in 90-100% of local PCa lesions, as well as in cancerous lymph nodes, and bone metastases, PSMA is a reliable tissue marker for PCa and is considered an ideal target for theranostic applications.

PCa lesions are found in 60% of the patients with PSA levels <2.2 ng/ml, while at PSA levels of >2.2 ng/ml, PCa lesions are found in all patients. Even at relatively low blood PSA levels, 68Ga- PSMA-PET/CT identifies lesions with high tumor-to-background ratios. In vivo, tumor uptake of 68Ga-PSMA is stable between 1 h and 3 h, while in normal tissue uptake slightly decreases between 1 and 3 h. As a result, late scans exhibit higher tumor-to-background ratios, which might be useful when lesions remain unclear in an early scan.

- Lütje S, PSMA Ligands for Radionuclide Imaging and Therapy of Prostate Cancer: Clinical Status; Theranostics 2015; 5(12): 1388-1401
- Chen Y , Foss CA, Byun Y, et al. Radiohalogenated prostate-specific membrane antigen (PSMA)-based ureas as imaging agents for prostate cancer. J Med Chem.2008;51:7933–7943.

Figure 9. [18F]-MISO

The majority of hypoxia PET tracers belong to a group of compounds termed nitroimidazoles.

18F-Fluoromisonidazole (18F-FMISO) was the first nitroimidazole-based radiotracer to be developed for hypoxia PET imaging.

Nitroimidazoles enter cells by diffusion and are reduced inversely correlated with oxygen tension. In the presence of oxygen they are able to leave the cell again, but under hypoxic conditions nitroimidazoles become reduced and will be irreversibly trapped within the cells.

18F-FMISO enters the cell by passive diffusion, where it is reduced by nitroreductase enzymes to become trapped in cells with reduced tissue oxygen partial pressure. When oxygen is abundant in normally oxygenated cells, the parent compound is quickly regenerated by reoxidation and metabolites do not accumulate. However, in hypoxic cells, the low oxygen partial pressure prevents reoxidation of 18F-FMISO metabolites, resulting in tracer accumulation. Because FMISO only accumulates in hypoxic cells with functional nitroreductase enzymes, FMISO will only accumulate in viable cells but not dead necrotic cells.

Quantification of 18F-FMISO ratioactivity in normal tissue achieves equality with plasma levels within 30 minutes, but selective retention of 18F-FMISO is observed in hypoxic tissue by 1 hour after injection and persists until 2.5 hours,  resulting in favorable information about the hypoxic volume being assessed.


- Lee ST, et al. Hypoxia Positron Emission Tomography Imaging With 18F-Fluoromisonidazole. Semin Nucl Med; 2007; 37:451-461.
- Li F, Joergensen J, et al. Kinetic modeling in PET imaging of hypoxia; Am J Nucl Med Mol Imaging 2014;4(6):490-506

Figure 10. [11C] and [18F]-ACETATE

In addition to increased glycolytic activity, several alterations of lipid metabolism are often found in cancer cells, including overexpression of fatty acid synthase (FAS).

HER2 signaling has also been implicated as a cause of increased FAS expression.
The mechanisms for apoptosis induced by FAS indicate that this apoptosis may be due to accumulation of FAS substrates triggering AMP-activated protein kinase.

FAS catalyzes the de novo synthesis of fatty acids from acetyl-CoA, malonyl-CoA, and nicotinamide adenine dinucleotide phosphate (NADPH). In the liver and adipose tissue, FAS serves to store energy derived from carbohydrate metabolism as triglycerides. In contrast, human cancer cells do not store significant amounts of triglycerides but esterify fatty acids to phospholipids, such as phophatidylcholine.
Fatty acids are activated to acyl-CoA and in a 2-step reaction form diacylglycerides with glycerol 3-phosphate. These diacylglycerides then react with CDP-choline to form phosphatidylcholine

Figure 11. [13N]-AMMONIA

Usage of 13N-ammonia with PET-CT enables an accurate, noninvasive quantification of regional myocardial perfusion. Its kinetic properties can be described in terms of a three-compartment model:

VASCULAR COMPARTMENT: characterizes the concentration of N-13 ammonia in  arterial blood

INTERSTITIAL COMPARTMENT: a conceptual space used to represent the extracellular N-13 ammonia in myocardial tissue.

CELLULAR COMPARTMENT: represents the accumulation of N-13 glutamine within the myocyte.

This model was developed under the following set of assumptions:

• The term “ammonia” refers to NH3 in chemical equilibrium with its charged species NH4+ (ammonium).

• 13N-ammonia behaves like a freely diffusible tracer across plasma and cell membranes.

• The extracellular and intracellular 13N-ammonia pools rapidly equilibrate.

• In bloodstream, 13N-ammonia exists primarily as NH4+, which can substitute for K+ on the sodium-potassium transmembranous exchange system, it thus may be actively transported into myocardium.

• Inside the myocyte NH4+ is converted to 13N-glutamine by glutamine synthetase and progressively accumulates. This process represents the main route for metabolic trapping and fixation of 13N-ammonia (and in a lesser degree, the ketoglutarate-glutamic acid reaction). Glutamine is then slowly released from the cell and serves as a carrier of ammonia for excretion.

• The available glutamine synthetase level remains essentially unchanged, so the ammonia molecules converted to glutamine remain constant.

• Both uptake and retention of 13N-ammonia in myocardium are primarily related to myocardial blood flow, therefore, at higher flows more 13N-ammonia diffuses back into the intravascular compartment and the fraction retained in the myocardium declines.
• Overall trapping of 13N-ammonia relies on intact metabolism, which may be impaired in ischemia and high cardiac work.

- Machac J; Radiopharmaceuticals for Clinical Cardiac PET Imaging; Cardiac PET and PET/CT Imaging; Springer; 2007; pp 73-82

- Muzik O, et al; Validation of Nitrogen-13-Ammonia Tracer Kinetic Model for Quantification of Myocardial Blood Flow Using PET; J Nucl Med. 1993;34:83-91.

- Hutchins GD, et al; Noninvasive quantification of regional blood flow in the human heart using N-13 Ammonia and dynamic PET imaging; JACC Vol 15, No. 5, 1990:1032-42

- Schelbert HR, et al; N-13 ammonia as an indicator of myocardial blood flow; Circulation. 1981;63:1259-1272

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