PET imaging of pancreas
The pancreas is a difficult organ to study because it is long and flat and hidden in the retroperitoneal space between the stomach and spine. The size of pancreas varies in humans, weighing 60 - 150 g, and it may even exist as two separate lobes (pancreatic divisum) in approximately 4-10% of the population. In animals, depending on the species, even up to three pancreases may exist, or there may not be a discrete pancreas at all (rabbits).
The pancreas has a nodular structure. The lobules are separated by connective tissue that contains the adipose tissue, blood vessels, lymphatics, excretory ducts, and nerves, and constitute ∼18% of the volume of the organ. Anatomically measured volume of pancreas is larger than volume measured using MRI or CT, mainly because of the interlobular fat tissue. Based on MRI studies, referred to by Majumder et al (2017), pancreatic fat content in healthy subjects is on average 2-5%, with high variance. Fat tissue, fibrosis, and atrophy of acinar cells is increased in older subjects. Pancreatic fat mass may increase by 70% in obesity, with ∼30% increase in the total pancreatic mass. In type 1 diabetes the pancreatic mass is decreased by 30-40% (Saisho, 2016). Exercise training reduced pancreatic fat in healthy, pre-diabetic, and type 2 diabetic men (Heiskanen et al., 2018).
The pancreas has exocrine and endocrine functions. Endocrine functions are located in separate cell clusters called islets of Langerhans. Exocrine functions include secretion of bicarbonate ions from centroacinar cells and digestive enzymes from basophilic cells into the intestine; about 1200 mL of fluid is produced daily. The exocrine portion constitutes about 80% of the pancreas. Towards the duct, the acinar cells have very tight junctions, preventing any reflux from the duct into the intercellular space. Elsewhere the cells have gap junctions, enabling fast communication and substrate exchange between the cells. Exocrine tissue has a normal arterial system, but in addition to that, it is also supplied by the blood leaving the islets of Langerhans.
Endocrine cells in pancreatic islets (0.025 - 0.4 mm in diameter) have a very dense capillary network around and inside them, and fenestrated endothelium enables direct contact with the blood in vessels. In healthy subjects ∼40% of the microvasculature in the islets are covered by pericytes, which participate in the control of local blood flow, and are innervated by sympathetic axons. In type 2 diabetes the pericyte coverage is decreased, contributing to poor control of islet blood flow (Richards et al., 2010; Almaça et al., 2018).
The blood from pancreatic islets goes to acinar cells (insulo-acinar portal system), enabling the hormones released in the islet to directly affect the exocrine system through a second capillary system (Lifson et al., 1980). Blood from pancreas and other abdominal visceral organs and gastrointestinal tract is drained via the portal vein into the liver, providing fast effect on the hepatic functions, and on the other hand allowing the liver to modify the systemic effects of pancreatic hormones.
Four main endocrine cells exist in the islets: α-cells secrete glucagon, β-cells secrete insulin, δ-cells secrete somatostatin, and γ-cells (PP cells) secrete pancreatic polypeptide. Total β-cell mass is about 1 g.
Endocrine functions are controlled by both sympathetic (adrenergic) and parasympathetic (muscarinic) innervation. Parasympathetic system stimulates insulin secretion, and sympathetic system stimulates glucagon secretion. Adrenergic input increases pericyte activity, reducing capillary diameter and blood flow (Almaça et al., 2018). Vasopressin stimulates the secretion of either insulin by β-cells or glucagon by α-cells, depending on the blood glucose level, by acting on vasopressin type 1B receptors. Insulin secretion is also stimulated by GIP, GLP-1, and CCK. Pancreatic cell can also directly sense the blood substrate levels; for example, β-cells respond to increasing blood glucose levels via GLUT2, and to the branched-chain amino acids (leucine, isoleucine, and valine) via LAT1. Activated β-cells inhibit pericytes via adenosine, dilating capillaries and increasing local blood flow. β-cells contain NMDA receptors (subtype of iGluRs in glutamatergic system), possibly regulating and/or taking part in β-cell depolarization.
Pancreatic islets can produce large quantities of GABA; it suppresses glucagon secretion in the α-cells, and increases insulin secretion in β-cells (Wan et al., 2015). Glutamate is co-released with glucagon from α-cells (Hayashi et al., 2003). Glutamine increases insulin secretion (Li et al., 2004).
Pancreatic islets receive nearly 20% of whole pancreatic blood flow, although they comprise only 2% (or 4.5%, depending on the source) of the pancreatic volume. In healthy humans the mean diameter is about 0.2 mm (0.025-0.4 mm). With the limited resolution of PET, the usual compartmental models with assumption of tissue homogeneity may not applicable to the pancreas. If that is the case, then the graphical analysis methods like Patlak and Logan plot would be more appropriate for analysis of pancreatic PET data. However, since the blood from islets is directed to other parts of the pancreas (insulo-acinar portal system), the tissue heterogeneity may only be a problem with certain radiopharmaceuticals or in cases when the relative fractions of direct arterial blood flow and blood flow via islets of Langerhans is changing.
Small size of islets prevents visualization of islets and direct assessment of their mass and function with PET, but measuring clinically relevant changes in the islet or β-cell density is an achievable goal (Cline et al., 2018).
Insulinomas are tumours that originate from the β-cells. These tumours secrete insulin, sometimes in such large quantities that the patient may be hypoglycaemic. GLP-1 receptors are overexpressed in benign insulinomas, and can be targeted for non-invasive localization of the tumours.
Since the volume of pancreas is highly variable, and reduces for example in T1D, it may be necessary to report the imaging results per whole pancreas in addition to the usual per mL tissue outcome.
Perfusion CT and [15O]H2O PET provide reliable quantification of pancreatic perfusion, despite a wide range of normal values as reviewed by Tsushima et al (2011). [15O]H2O PET results have been reported by Kubo et al (1991), Honka et al (2014 and 2015), and Lauritsen et al (2020) for pancreas, and by Komar et al (2009) for pancreatic cancer. Because of the insulo-acinar portal system and the fast distribution of [15O]H2O between the blood and tissue, it is probable that only a lumped estimation of exocrine and endocrine perfusion can be obtained with that radiotracer.
Nalin et al. (2014) reported perfusion values ∼0.45 mL/(mL*min) in the pancreas of healthy pigs and ∼0.35 mL/(mL*min) in diabetic pigs.
Glucose uptake (GU) has been quantified in pancreas using [18F]FDG and Patlak plot (Kalliokoski et al., 2008; Heiskanen et al., 2018) or FUR analysis (Honka et al., 2014). Semiquantitative FDG has been used in oncology; FDG PET can detect pancreatic carcinoma (van Kouwen et al., 2005), and predict disease-free survival in patients with resectable pancreatic cancer (Omiya et al., 2018).
Fatty acid uptake
[11C]Methionine uptake in the pancreas has been quantified using irreversible two compartment model and Patlak plot, both providing similar net influx rates (Kalliokoski et al., 2008). [11C]Methionine has also been used to study exocrine pancreatic function.
[11C]Acetate has been used to visualize the exocrine pancreas, based on its uptake by anion transporters in acinar cells (Shreve and Gross, 1997; Hyun O et al., 2014). Uptake in the pancreas is high, with SUV of ∼6.4 (Malkowski et al., 2017).
Dopamine is co-secreted with insulin from β-cells, and can bind to dopamine receptors on β-cells (Ustione et al., 2013). L-DOPA (L-3,4-dihydroxyphenylalanine) treatment in Parkinson's disease reduces insulin secretion, while dopamine antagonists increase insulin secretion. D2Rs are expressed on both exocrine and endocrine pancreas, while D3Rs are found almost exclusively in β-cells, with very little expression in exocrine pancreas (Bini et al., 2018). Accordingly, [11C](+)PHNO, with 2:1 binding of D3Rs over D2Rs, shows some promise in assessment of β-cell mass (Bini et al., 2018).
L-DOPA is a precursor of catecholamines that is converted to dopamine by AADC in pancreatic islets (Ericson et al., 1977; Lindström, 1986; Borelli et al., 1997; Ustione & Piston, 2012). Radiofluorinated analogue of L-DOPA, [18F]FDOPA, has been used to assess the altered AADC activity in pancreas in patients with congenital hyperinsulinism (Mohnike et al., 2006), and to distinguish between focal and diffuse forms of hyperinsulinism in infancy (Ribeiro et al. 2007). [18F]FDOPA PET may be useful in detecting focal nesidioblastosis (Andralojc et al., 2012), and for imaging transplanted islet mass (Eriksson et al., 2014a). [18F]FDOPA uptake in islets and exocrine pancreas does not differ, not even after using various enzymatic inhibitors of DOPA metabolism pathways (Kalliokoski et al., 2014), although generally the uptake patterns of L-DOPA analogues can be modified with inhibitors (Bergström et al., 1997). A metabolite of [18F]FDOPA, [18F]OMFD, has been studied as marker of amino-acid transport activity in tumours, and it has high uptake in pancreas (Haase et al., 2007). At least the late accumulation phase is due to decarboxylation, because carbidopa (AADC inhibitor) administration prevents the accumulation (Ribeiro et al., 2005).
β-cell mass and function
Islets constitute only about 1% of the pancreatic mass. It is estimated that for quantifying β-cell mass (BCM) the PET radiopharmaceutical should accumulate in ratio 100:1 in β-cells compared to other pancreatic tissue (Sweet et al. 2004); this hardly can be achieved with any dopamine related compound, because also exocrine cells produce and store DOPA and dopamine (Mezey et al. 1996). Regardless of the intrinsic challenges, development of imaging biomarkers for β-cell mass and function is going on, because of the importance in the study of type 1 and 2 diabetes mellitus and insulin resistance (Ichise and Harris, 2010; Leibiger et al., 2012; Andralojc et al., 2012; Yagihashi, 2012; Karlsson et al., 2015; Yang et al., 2017).
Vesicular monoamine transporter type 2 (VMAT2) is expressed by β-cells and monoaminergic neurons, but is not found in the exocrine pancreas. VMAT2 targeting PET radioligands, including [11C]DTBZ, [18F]FE-DTBZ, [18F]FP-DTBZ, and [18F]AV-133 have shown uptake in pancreas; however, quantification the specific uptake in the pancreas has been difficult (Goland et al., 2009; Fagerholm et al., 2010; Eriksson et al., 2010; Tsao et al., 2011; Freeby et al., 2012; Normandin et al., 2012; Harris et al., 2013). Because of the low BCM, even relatively small concentrations of parent radiopharmaceutical or label-carrying metabolites in the exocrine pancreas or tissue vasculature may lead to large bias in estimates of specific binding. Spleen has been suggested to be suitable pseudo-reference region in calculation of SUV ratio in [18F]FP-(+)-DTBZ studies (Naganawa et al., 2016 and 2018; Cline et al., 2018).
GLP-1R is mainly expressed on β-cells, with low levels on α-cells and gastric parietal cells. GLP-1R specific PET radiopharmaceuticals, such as [18F]Exendin-4, have potential to assess the β-cell mass.
Pancreatic β-cells and several neuroendocrine tumours express somatostatin receptor SSTR1. Somatostatin analog [68Ga]DOTANOC has prognostic value in non-functional pancreatic neuroendocrine tumours (Majala et al., 2019).
Glucokinase (GK) is an isozyme to hexokinase, predominantly present in the β-cells and in hepatocytes in the liver. GK is regulated by glucokinase activators (GKAs), small molecules which stabilize the bound state between GK and its substrates. GKAs have been considered as a promising target for drug development, providing also candidates for PET radiopharmaceutical development. [11C]AZ12504948 was not sufficiently specific to GK to be useful for imaging BCM, and it was also not optimal radiopharmaceutical for quantitation of GK in the liver (Jahan et al., 2015).
Prostaglandin D2 receptor 2 (PTGDR2, CRTH2, GPR44, CD294) is expressed on certain white blood cells, especially Th2-cells, in spleen, and in the central nervous system. In pancreas, the expression is restricted to the β-cells. PTGDR2 antagonist AZD3825 has been shown to specifically bind to β-cells and human islet preparations with very little binding in exocrine pancreas. Its structural analogue [11C]AZ12204657 shows specific PTGRD2 binding in pancreas and spleen of pigs and nonhuman primates (Eriksson et al., 2018a) and in vitro in human pancreatic tissue (Jahan et al., 2018).
Functional β-cells internalize divalent metal ions through voltage-dependent Ca2+ channels (VDCCs). Ca2+ flux has been used in in vitro β-cell studies. Manganese mimics Ca2+ and is transported through VDCCs; [52Mn]Mn2+ PET can be used to detect changes in BCM in mouse model of diabetes (Hernandez et al., 2017). The zinc transporter 8 (ZnT8) may also be a suitable target for imaging BCM (Eriksson et al., 2018b).
Synaptic vesicle glycoprotein 2 A (SV2A) is highly expressed in endocrine pancreas. PET radioligands targeting SV2A have been used to assess synaptic density in CNS, and could potentially be used for imaging islets of Langerhans. [11C]UCB-J was not found sensitive for this purpose in animal studies (Puuvuori et al., 2021).
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Updated at: 2023-02-02
Created at: 2014-06-17
Written by: Vesa Oikonen