Radiopharmaceuticals and contrast agents

Introduction and mechanism of uptake

FDG is a marker of glucose metabolism and the most widely used PET radiopharmaceutical worldwide ( ; ). FDG is incorporated into the cells through a family of glucose transporters (GLUT) and is subsequently phosphorylated by the hexokinase enzyme ( ; ). The resultant product, FDG-6-Phosphate, is trapped intracellularly without undergoing further metabolism.

Most tumors demonstrate increased glucose metabolism, a feature exploited by FDG PET for oncologic imaging, due to overexpression of membrane glucose transporters (especially GLUT-1 and GLUT-3) and increased hexokinase activity. Additionally, neoplasms often exhibit decreased levels of glucose-6-phosphatase ( ).

However, increased FDG uptake is not restricted to malignancies, since several benign pathologies/conditions demonstrate increased glucose metabolism, which could act as a confounder in tumor imaging ( ). Such processes include active inflammation, hypermetabolic brown fat, and muscular activity ( ). Therefore, the diagnosis of malignancy needs to be established in the proper clinical and imaging context. Additionally, the metabolic activity of tumors can vary, resulting in variable PET appearance.

Indications/uses

FDG PET is commonly used for diagnosis, staging, and restaging of tumors, treatment response evaluation, and radiation and surgical planning. Common oncologic applications include evaluation of a wide range of malignancies such as lymphoma, lung cancer, head and neck malignancies, gastrointestinal cancers, melanoma, and multiple myeloma among others. Some of the most common nononcologic indications include work-up of fever of unknown origin, vasculitis, sarcoidosis, vascular graft infection, dementia, seizures, and assessment of myocardial viability ( ; ).

Patient preparation

While specific recommendations vary by institution and clinical indications, some general guidelines are provided below ( ; ):

Radiopharmaceutical administration and postinjection wait period

The radiopharmaceutical is administered intravenously. An incubation period of approximately 60 min is usually recommended for radiopharmaceutical uptake and distribution throughout the body. Ideally, the patient should stay in a seated or recumbent position in a quiet dimly lit and warm room.

Normal biodistribution

Variable degrees of uptake could be seen in different organs and regions as shown and discussed below ( Fig. 2.1 ) ( ; ):

Head and Neck: intense physiologic uptake is usually seen in the cerebral cortex and basal ganglia. Variable degrees of uptake are seen in lymphatic tissues including the tonsils and Waldeyer's ring, more prominent in young patients. Variable degrees of uptake can be seen in the ocular muscles, muscles of mastication, and the tongue. Variable but usually low-level uptake is seen in the salivary glands and vocal cords. Phonation could result in intense vocal cord uptake.

Thorax: There is usually low-level uptake to mediastinal structures with variable uptake to the thymus, glandular breast tissue and the spinal cord, particularly at the level of T12-L2. Marked uptake in the breasts is usually seen in lactating mothers. Myocardial uptake is dependent on fatty acid metabolism. However, in the cases of hyperinsulinemia, including the nonfasting state, the myocardium switches to glucose metabolism and intense uptake in the myocardium could be seen. Therefore, myocardial uptake is very variable and can range from completely suppressed to very intense, depending on the dietary preparation.

Abdomen/pelvis: splenic uptake is usually similar to or less than the liver. FDG is usually filtered by the glomeruli resulting in significant activity in the renal collecting system, ureter, and bladder. Additionally, there is typically moderately intense physiologic uptake in the renal parenchyma. The stomach may show low-level homogenous uptake. Diffuse nonfocal variable uptake to the bowel is common. High uptake is usually observed in the colon followed by the small bowel. Symmetric diffuse testicular uptake and faint uterine activity are commonly seen. Besides FDG uptake in the case of corpus luteum, ovarian uptake is not common.

Skeleton and soft tissues: bone marrow normally shows low-level uptake that is less intense than the liver in the absence of conditions that lead to bone marrow stimulation. However, the patient's receiving granulocyte colony-stimulating factor (G-CSF) may have increased bone marrow and splenic activity. Rested/relaxed skeletal muscles typically do not demonstrate significant uptake. Increased skeletal muscle uptake could be seen after physical activity and/or in the setting of hyperinsulinemia, usually due to nonfasting state, as insulin increases muscle uptake. Multiple nonmalignant processes could result in osseous and/or soft tissue uptake including degenerative changes, fractures, postoperative changes, biopsy sites, etc.

Brown adipose tissue: inactive brown fat shows no significant FDG uptake. However, metabolically active brown fat is intensely avid. Brown fat is activated by cold temperatures. Children have high brown fat stores, which classically decline with age. The typical distribution of brown fat is symmetric and includes the neck, supraclavicular, axillary, mediastinal, paraspinal, and upper abdominal perinephric, para-aortic, and suprarenal regions ( Fig. 2.2 ). Brown fat could potentially obscure suspicious findings in these regions; therefore, careful evaluation of these areas on anatomic imaging is encouraged. These areas of uptake should correspond to fat density on CT and MRI. Keeping the patient warm is the easiest approach to minimize brown fat hypermetabolism. However, certain pharmacologic interventions could also be utilized, including the administration of diazepam ( ) and beta-blockers such as propranolol ( ).

Pitfalls

As mentioned earlier, any process that results in glucose hypermetabolism could cause elevated FDG uptake ( ). Such nonmalignant processes include some benign tumors (such as some bowel adenomas, benign parotid tumors, renal oncocytoma), infectious processes, noninfectious inflammatory processes (such as colitis, vasculitis, and IgG4-related disease), granulomatous disease such as sarcoidosis ( Fig. 2.3 ), hyperplasia or dysplasia (such as Cushing's disease, Paget's disease, and bone marrow hyperplasia in the setting of anemia), postoperative and posttraumatic changes, and other conditions (such as Erdheim-Chester disease). Additionally, physiologic uptake may lead to false-positive interpretations such as brown fat hypermetabolism, lymphoid tissue uptake, thymic uptake especially in children, and endometrial uptake during menstruation and ovarian uptake in premenopausal women ( ).

Many tumors are not particularly very FDG-avid, which can lead to false-negative reads ( ). These include low-grade tumors such as low-grade lymphomas, predominantly mucinous tumors, some hepatocellular carcinomas (HCCs), well-differentiated prostate adenocarcinoma and neuroendocrine tumors. Other causes of false-negative interpretation include small lesion size, tumor necrosis, ground-glass pulmonary nodules, hyperglycemia and/or hyperinsulinemia, and recent high-dose steroid therapy.

Introduction and mechanism of uptake

68Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated peptides target somatostatin receptors (SSTR), which are expressed in several normal tissues as well as in neoplasms, such as neuroendocrine tumors (NETs) ( ). The different subtypes of 68Ga-DOTA-conjugated peptides, while demonstrating diverse affinity toward the various SSTR subtypes, all bind to SSTR2. The most commonly used radiopharmaceuticals are SSTR agonists ( ; ; ; ; ) such as:

• -

  68Ga-DOTATOC ([68Ga-DOTA0 -Tyr3] octreotide): Binds predominantly to SSTR2, and SSTR5 (with lower affinity compared to DOTANOC).

• -

  68Ga-DOTANOC ([68Ga-DOTA0-1NaI3] octreotide): Has a higher affinity for SSTR2, although it also shows a high affinity for SSTR3 and SSTR5 compared to 68Ga-DOTATATE.

• -

  68Ga-DOTATATE Octreotate ([68Ga-DOTA0 -Tyr3] octreotate): Has a high affinity for SSTR 2, and higher physiological uptake in the pituitary and salivary gland compared to 68Ga-DOTANOC.

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  68Ga-DOTA-lanreotide: Binds to SSTR2 and SSTR5.

64Cu-DOTA-TATE, an additional radiopharmaceutical, has favorable positron energy (maximum positron energy: 0.653 MeV). In addition, it has a considerably lower positron range than 68Ga (maximum positron energy, 1.899 MeV). 64Cu-DOTATATE has shown advantages over 68Ga-DOTATOC in the evaluation of NETs, as significantly more lesions may be detected by 64Cu-DOTATATE PET ( ).

Indications/uses

SSTR targeting radiopharmaceuticals are used for the detection of well- or moderately differentiated NETs that express SSTR(s), most of which predominantly express SSTR2. PET imaging could be performed for diagnosis, initial staging, restaging, or evaluation of treatment response. In addition, it is used as a prognostic tool to select candidates for treatment with somatostatin analogues or SSTR-targeting radionuclide therapy ( ; ).

Patient preparation

Although specific recommendations vary by institution and clinical indication, some general guidelines are as follows:

• 1

  Withdrawal of somatostatin analog medications, when possible and not contraindicated, to avoid potential SSTR blockade 1 day prior to PET for short-acting SSTR analogs and at least 3–4 weeks prior to PET for long-acting analogs. These recommendations are currently not standardized worldwide ( ).

• 2

  Dietary preparation:

  • (a)

    Fasting is not necessary prior to radiopharmaceutical injection ( ).

  • (b)

    Hydration: adequate hydration is recommended prior to imaging to maintain low serum and urine concentration of the radiopharmaceutical and to limit the radiation dose to the renal collecting system and bladder, which are the critical organs.

• 3

  Immediately prior to image acquisition, patients are asked to void to help eliminate urinary excreted 68Ga not bound to peptides, thus reducing background noise, and decreasing the genitourinary radiation dose ( ).

Radiopharmaceutical administration and image acquisition

The radiopharmaceutical is administered intravenously. After injection of the radiopharmaceutical, an incubation period of approximately 60 min is usually recommended for radiopharmaceutical uptake and distribution throughout the body.

Normal biodistribution

SSTRs are expressed in many neuroendocrine and nonneuroendocrine cells in the body resulting in 68Ga-DOTA-conjugated peptides accumulation in several normal organs ( Fig. 2.4 ). Physiological 68Ga-DOTATATE biodistribution is described below ( ; ).

Head/Neck: intense physiologic uptake is observed in the pituitary gland, with mild to moderate uptake in the salivary glands and thyroid.

Thorax: breast glandular tissue may show diffuse low-grade physiological uptake.

Abdomen/pelvis: marked physiologic uptake is shown in the spleen, kidneys, adrenals and liver. The highest physiologic uptake is usually seen in the spleen, which is the critical organ ( ). Variable moderate uptake is observed in the stomach wall and intestine. The pancreas shows variable uptake of 68Ga-DOTA-conjugated peptides. Although all five SSTR subtypes are present in the pancreas, SSTR2 receptors are preferentially localized in the islets. The higher concentration of islets cells in the head and uncinate process of the pancreas results in intense physiological uptake in this region. The prostate gland may demonstrate mild diffuse uptake.

Skeleton and soft tissues: musculoskeletal uptake is usually low/negligible.

PET interpretation

Different tumor histotypes have variable degrees of DOTA radiopharmaceuticals uptake ( ).

• 1.

  Tumors typically with high SSRT expression level: Functioning and nonfunctioning gastro-entero-pancreatic NET (e.g., gastrinoma, insulinoma glucagonoma, VIPoma), NET of the lungs, tumors of the sympathetic-adrenal system (e.g., paraganglioma) and meningioma.

• 2.

  Tumors typically with low or variable expression of SSTRs: Breast carcinoma, melanoma, lymphoma, prostate carcinoma, nonsmall cell lung cancer, head and neck tumors, sarcoma, renal cell carcinoma, differentiated thyroid carcinoma and astrocytoma.

Pitfalls

68Ga-DOTA radiopharmaceuticals demonstrate high physiological uptake to the uncinate process of the pancreas, spleen, pituitary gland, kidneys and adrenal glands, which limits evaluation for underlying pathologies in these regions. Some nonneoplastic conditions can also induce increased uptake, particularly inflammation (e.g., prostatitis, postradiation changes, reactive lymph nodes), bone remodeling (e.g., osteoarthritis and recent fractures), fibrous dysplasia, epiphyseal growth plates and splenosis. In addition, some benign neoplasms could demonstrate uptake (e.g., meningiomas, osteomas and hemangiomas).

Endogenous somatostatin production by the tumor(s) and exogenous somatostatin analogue therapy by short- or long-acting octreotide may interfere with the degree of DOTA peptide uptake by the tumors, which could result in a false-negative read. Tumor differentiation level and inter and intratumoral heterogeneous SSTR expression, and small lesion size (<5 mm) may also lead to false-negative results ( ).

Introduction and mechanism of uptake

Anti-1-amino-3-fluorocyclobutane-1-carboxylic acid labeled with [18F]Fluorine (also known as 18F-Fluciclovine or 18F-FACBC) is an FDA approved prostate cancer imaging agent. 18F-fluciclovine is an amino acid (leucine) analog, which shows high uptake in cancer cells due to increased protein turnover ( ). Currently, 18F-fluciclovine is mainly used for the evaluation of patients with biochemical recurrence of prostate cancer. The sensitivity for detecting recurrent disease increases with higher Gleason scores and higher prostate specific antigen (PSA) levels ( ; ). Sensitivity reaches up to 85% at PSA levels above 6 ng/mL ( ). 18F-fluciclovine PET is highly sensitive but not very specific for detecting local recurrence within the prostate gland as intraprostatic uptake could be benign or due to residual cancer. In addition, 18F-fluciclovine PET alone underperforms in detecting the osseous metastatic disease when compared to bone scintigraphy or combined 18F-fluciclovine PET/MRI ( ).

Indications/uses

18F-Fluciclovine is currently used for suspected prostate cancer recurrence.

Patient preparation

Fasting for at least 4 h is usually recommended. Strenuous exercise should be avoided for at least a day before the study as it could lead to an increase in protein synthesis and muscle uptake ( ).

Following the study, the patient should remain hydrated and urinate frequently in order to reduce the radiation exposure to the bladder.

Radiopharmaceutical administration and image acquisition

18F-Fluciclovine is administered intravenously and is rapidly taken up by prostate cancer cells. The tumor-to-background ratio is the highest between 1 and 15 min postadministration ( ). Therefore, early image acquisition is encouraged, ideally within 3–5 min after injection of 18F-fluciclovine. PET scanning proceeds from the proximal thigh toward the base of the skull to minimize urinary accumulation of the radiopharmaceutical in the bladder, which could obscure suspicious findings ( ).