Clinical Radiology 65 (2010) 536e548 Contents lists available at ScienceDirect Clinical Radiology journal homepage: www.elsevierhealth.com/journals/crad Non FDG PET C. Nanni*, L. Fantini, S. Nicolini, S. Fanti Nuclear Medicine Unit, Policlinico S.Orsola, University of Bologna, Bologna, Italy article in formation Article history: Received 30 October 2009 Received in revised form 9 March 2010 Accepted 15 March 2010 2- [18F]-fluoro-2-deoxy-D-glucose (FDG) is the radiopharmaceutical most frequently used for clinical positron emission tomography (PET). However, FDG cannot be used for many oncological, cardiological, or neurological conditions, either because the abnormal tissue does not concentrate it, or because the tissues under investigation demonstrate high physiological glucose uptake. Consequently, alternative PET tracers have been produced and introduced into clinical practice. The most important compounds in routine practice are 11C-choline and 18 F-choline, mainly for the evaluation of prostate cancer; 1C-methionine for brain tumours; 118 F-DOPA (18F- deoxiphenilalanine) for neuroendocrine tumours and movement disorders; 68 Ga-DOTANOC (tetraazacyclododecanetetraacetic acid-[1-Nal3]-octreotide) and other somatostatin analogues for neuroendocrine tumours; 11C-acetate for prostate cancer and hepatic masses and 18F-FLT (3-deoxy-3-fluorothymidine) for a number of malignant tumours. Another impetus for the development of new tracers is to enable the investigation of biological processes in tumours other than glucose metabolism. This is especially important in the field of response assessment, where there are new agents that are targeted more specifically at angiogenesis, hypoxia, apoptosis and other processes. Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Introduction Since its introduction into clinical practice, positronemission tomography (PET) has been associated with the use of 2- [18F]-fluoro-2-deoxy-D-glucose (FDG). FDG, a glucose analogue, has a very high sensitivity for the detection of malignant involvement by more than 90% of tumours, and has proved to be useful in staging,1 re-staging,2 assessing therapy response 3,4 and during follow-up.5,6 Furthermore, FDG can be employed for the identification of several types of dementia,7,8 where imaging abnormalities can significantly precede the onset of clinical signs, and in the evaluation of cardiac viability.9 Despite the large field of application for FDG, some malignant tumours (for example, prostate cancer,10 neuroendocrine tumours,11 hepatic tumours 12 and others) * Guarantor and correspondent: C. Nanni, UO Medicina Nucleare, Ospedale S.Orsola-Malpighi, Via Massarenti n.9, 40138 Bologna, Italy. Tel.: þ39(0) 51 6363187. E-mail address: cristina.nanni@aosp.bo.it (C. Nanni). frequently do not show a significantly increased FDG uptake and, therefore, may be undetectable by FDG PET. Furthermore, FDG presents two major drawbacks in oncology: it is not useful for evaluating malignant masses that are located in tissues with physiologically high glycolytic metabolism (for example, central nervous system tumours) 13 and cannot distinguish between inflammation and cancer,14,15,16 as both processes are characterized by increased glucose metabolism. Similarly, FDG is not suitable for diagnosing patients with movement disorders, while in cardiology it cannot be used to evaluate coronary blood flow 17 due to its low first-pass extraction. For these reasons, expansion of the pool of PET tracers available for use in oncology, neurology, and cardiology was considered of primary importance and several other compounds have been tested. Of these new tracers, the most important in current clinical practice are: choline (11C- and 18F-labelled); 11 C-methionine; 18F-DOPA; 68Ga-DOTANOC and other somatostatin analogues; 11C-acetate and 18F-FLT (3-deoxy3-fluorothymidine). 0009-9260/$ e see front matter Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.crad.2010.03.012 C. Nanni et al. / Clinical Radiology 65 (2010) 536e548 The aim of this paper is to provide a concise overview of the most commonly used non-FDG tracers in clinical use and reviews the most promising developments in the field. 11 C-Choline As stated above, well-differentiated prostate cancer is one the most clinically important low glucose-utilizing tumours. Furthermore, the frequent co-existence of inflammatory processes in the prostate and the gland’s close proximity to the bladder with its contained urinary activity, result in difficulties when using FDG to diagnose primary prostate cancer or, more importantly, to assess prostate cancer local relapse with FDG.18,19 11 C-choline is a small molecule that, once injected intravenously, is very quickly integrated in the cell membrane as phosphatidilcholine and is a marker of membrane metabolism. 11C-choline is subject to very late urinary excretion, so that the pelvis is free from urinary radioactivity at the time of image acquisition. Unlike FDG, 11 C-choline has been shown to have a high affinity for malignant prostate tissue, including low-grade tumours. Several studies have analysed the role of 11C-choline PET/ CT for the evaluation of prostate cancer, suggesting that the 537 most cost-effective use is in the diagnosis of prostate cancer relapse. Following radical treatment for prostate cancer with surgery or radiotherapy, patients presenting with rising prostate-specific antigen (PSA) serum level and negative conventional imaging procedures [trans-rectal ultrasound, bone scintigraphy, and pelvic magnetic resonance imaging (MRI)] can benefit from 11C-choline PET, which performs well in the early detection of nodal involvement (sensitivity 80%; specificity 96%; accuracy 93%) and in the detection of secondary bone lesions. Bone involvement can be detected before standard bone scintigraphy becomes abnormal as the 11C-choline uptake in malignant metastatic cells occurs in advance of osteoblast activation. 11C-choline PET is also useful for local recurrence detection, but with a lower sensitivity 20,21(Fig. 1). In recent years several authors have demonstrated that the positivity of 11C-choline PET is related to the serum levels of PSA. Castellucci et al.22 also found that PSA-velocity strongly influences the probability of positive findings on PET, as it is related in some way to the malignancy of the disease relapse (the higher the PSA velocity, the faster the prostate cancer lesion is growing). Finally, Farsad et al. studied 11C-choline PET efficacy in the detection of intra-prostatic primary cancer and demonstrated that for this indication it is very non-specific Figure 1 A patient with a metastatic prostate cancer. Choline PET is positive for multiple bone lesions before therapy (a) and showed a complete response after the onset of hormonal therapy (b). 538 C. Nanni et al. / Clinical Radiology 65 (2010) 536e548 and must be used only for selected patients at high risk with multiple negative biopsies. In fact, every intra-prostatic focal pathological process (including benign prostatic intraepithelial neoplasia, adenomas, intra-prostatic hyperplasia, or prostatitis) shows increased 11C-choline uptake exactly like prostate cancer.23 Another interesting preliminary application of 11Ccholine is in the evaluation of patients with skeletal involvement from multiple myeloma. In a series of 10 patients who were evaluated both with 11C-choline and FDG, choline detected more lesions. However, the difference between the detection rate of the two tracers was not statistically significant.24 To conclude, 11C-choline PET is a useful test in the investigation of patients with radically treated prostate cancer, rising PSA levels and negative conventional imaging. Furthermore, a new possible indication for the examination seems to be in the restaging of patients with only one demonstrable site of prostate cancer relapse, in order to strengthen the indications for local therapy and avoid the need for systemic treatment. 18 F-choline The major drawback of 11C-choline is the very short halflife of the isotope (20 min). This means that this interesting tracer cannot be sent out from the production site, and that only PET centres with an on-site cyclotron can use it. For this reason, several authors have based their functional imaging of prostate cancer on the use of 18F-choline, which is a PET tracer with a much longer half-life (120 min) that can be delivered to PET centres without their own cyclotron. When 18F-choline was proposed for diagnostic use, there was concern that the introduction of a very electronegative atom like 18F into the molecule would deform the structure of choline and change its physiological properties. In addition, the longer uptake time (usually 60 min) would allow renal excretion of the tracer into the urinary bladder, complicating image interpretation in the pelvis. The clinical indications for the use of of 18F-choline are exactly the same as for 11C-choline.25e27 The restaging of disease in patients with rising levels of PSA and negative conventional imaging is by far the most appropriate indication, although several groups have assessed its utility in the diagnosis of primary prostate cancer, especially in patients with negative biopsy and serum marker levels suggestive for cancer, with variable results.28e30 As with 11 C-choline, Schmid et al. did not find any difference in uptake between benign prostatic conditions (especially hyperplasia) and cancer, while Reske et al. found a significantly higher uptake in primary prostate cancer.31, 32 Unfortunately, no data are available on the direct comparison between 11C-choline and 18F-choline accuracy, although the sensitivity of the two tracers seems to be broadly comparable. 18 F-choline has also been used of the evaluation of hepatocellular carcinoma (HCC), as FDG is known to be insensitive in this context, especially for well-differentiated HCC. In a small series of 12 patients, 18F-choline was positive in 12 out of 12 patients while FDG was positive in five out of nine patients.33 Of course these results are too preliminary to draw any conclusions, but this application is theoretically interesting due to the many problems of imaging HCC. 11 C-methionine The excellent soft-tissue contrast provided by MRI and the range of sequences available for exploring differences in the biophysical properties of normal brain tissue and cerebral tumours, has made MRI the imaging method of choice for the assessment of brain tumours. However, MRI has proved not to be accurate enough in the detection of infiltrating glioma cells, making it difficult to delineate accurately tumour extent.34 As a result, a wider margin must be added to radiotherapy treatment volumes to account for these infiltrating cells. As this margin includes normal brain, the total dose used has to be reduced to reduce the risk of radiation necrosis. As a consequence, gliomas recur within the treatment volume in the majority of patients. Conventional MRI is also relatively ineffective in the evaluation of tumour grading. Histology is the reference standard in characterizing brain tumours, but it is well known that biopsies have an appreciable morbidity and mortality. MRI can correctly classify high-grade tumour with 65% sensitivity and 95% specificity. For low-grade gliomas, studies suggest that only half are correctly classified using MRI and that one-third of non-enhancing tumours are in fact high-grade gliomas. Additionally, there is now evidence that the early detection of tumour recurrence at an asymptomatic stage is associated with improvements in patient survival, and delay in determining that a treatment has failed may result in the patient being too ill to be considered for second-line therapy.35 However, while conventional imaging procedures (contrast CT and MRI) are useful in the detection of disease relapse, the differentiation between tumour and benign conditions such as post-surgical fibrosis, radionecrosis and oedema is sometimes very difficult or even impossible. The brain exhibits intense physiological uptake of FDG because glucose is the main metabolic substrate for the central nervous system (CNS). Consequently, small malignant lesions are very difficult to detect with FDG PET as they may be masked by the hypermetabolic background.36,37 11 C-methionine is a radiolabelled amino acid that does not accumulate in normal brain. Benign conditions, such as fibrosis, necrosis, or oedema, are also cold. On the contrary, malignant lesions (even if low-grade) do exhibit increased 11 C-methionine uptake due to an increased protein metabolism and vascular permeability. This low or absent background activity in normal brain tissue and benign conditions, and the marked capacity of malignant lesions to accumulate 11C-methionine, makes it a very useful radiotracer for the study of malignant CNS tumours. The most appropriate indication is when conventional imaging procedures are unable to discriminate between disease relapse and oedema, fibrosis or necrosis. In this case, 11C-methionine PET significantly shortens the time to diagnosis, allowing prompt second line treatment. Furthermore, the uptake of 11C-methionine is C. Nanni et al. / Clinical Radiology 65 (2010) 536e548 proportional to tumour grade,38e41 and therefore, the maximum SUV inside the brain mass before therapy can have prognostic value. In summary, although brain tumours are characterized by an increased FDG uptake, for reasons mentioned above, image interpretation is much more difficult than it is with 11 C-methionine.37, 42 Furthermore, 11C-methionine is the only tracer whose uptake positively correlates with grade, type, and proliferative index (Figs. 2 and 3). Recently, advanced MRI has been applied to the clinical management of patients affected by brain tumours. Diffusion-weighted imaging and perfusion imaging are two MR techniques that permit the study of pathological and biological changes within tumours, and could potentially be associated with 11C-methionine PET in the diagnostic algorithm for brain tumours. The literature in this field is still at a very preliminary stage, and a direct comparison between the performance of 11C- methionine PET and advanced MR is only found in a few papers. According to the published data, it seems that advanced MR and 11Cmethionine PET are equally effective in differentiating radiation effects from tumour recurrence or progression. However, a larger series of patients is required to define the relative indications for these imaging methods.43 Other applications of 11C-methionine PET are possible. Some groups have used this tracer to obtain better definition of radiotherapy fields both for CNS tumours and head and neck tumours, to localize the most metabolically active area inside a brain mass to guide biopsy 44 or for the early evaluation of radiotherapy efficacy in head and neck cancer (using the low uptake of 11C-methionine in inflammatory tissue).45 It has also been used in the evaluation of patients with primary, secondary, and tertiary hyperparathyroidism,46e49 although it has not yet been introduced to clinical practice, and remains a research application. In a significant number of patients affected by hyperparathyroidism conventional imaging (neck CT, MRI, neck ultrasound, dual-tracer scintigraphy) fails to identify the hyperactive parathyroid glands and and so does not help to guide surgery. Recent papers have examined a possible role for 11C-methionine PET/CT for the identification of hyperfunctioning parathyroids. This imaging technique exploits the combination of the special resolution and anatomical localizing capacity of the CT and the functional information provided by PET. The literature is inconclusive, as the reported sensitivity ranges from 92% 50 to 35% 51 for adenomas, and in some papers, the sensitivity is inferior to that of dual-tracer scintigraphy. Therefore, based on the published data, 11C-methionine PET/CT does not have a proven role in the diagnostic algorithm for hyperparathyroidism, and more research is required. 18 F-DOPA 18 F-deoxiphenilalanine is a radiolabelled amino acid precursor of dopamine. It was synthesized for the in vivo evaluation of striatal activity in patients with suspected Parkinson’s disease (PD), but recently it has also been 539 Figure 2 A patient with a brain lesion detected at MRI suspected to be a CNS malignant tumour but the patient had no history of previous malignancy. Methionine PET was negative. After 1 year follow-up the patient remains stable. The negative 11C-methionine PET was useful to diagnose a non-malignant finding. (a) MRI; (b) fusion CT; (c) methionine PET/CT. employed in oncology for the detection of malignant tumours derived from neural crest tissue.52 Such tumours (carcinoid, pheocromocytoma, neuroblastoma, medullary thyroid cancer, microcytoma, carotid glomus tumours, and 540 C. Nanni et al. / Clinical Radiology 65 (2010) 536e548 Figure 3 A patient with a suspected relapse of glioblastoma at MRI (a). This finding was stable for 5 months. 11C-methionine PET (B) was positive, indicating a relapse. 18F-FDG (C) was also positive but the contrast resolution was inferior to that of methionine PET. melanoma) are usually very well-differentiated and 18FFDG PET has proved to be insensitive in their detection. When conventional imaging is negative in patients with specific syndromes connected to this type of neoplasia, 111 In-octreoscan single photon-emission computed tomography (SPECT) or 123I-metaiodobenzylguanidine (I-MIBG) SPECT are performed to detect both primary and secondary lesions and to evaluate disease relapse. These tests have good sensitivity and specificity, but the spatial resolution is poor compared to that obtainable with PET imaging. This means that small lesions may be missed. As these tumours have the capacity to concentrate amino acids inside the cytoplasmatic space through a metabolic mechanism, 18F-DOPA was tried as specific tracer and turned out to have a very good sensitivity and specificity, probably higher than conventional imaging procedures 53e57 (Fig. 4). Despite promising preliminary results, the literature in this area is still very sparse, as the synthesis of this compound is difficult and neuroendocrine tumours are relatively rare. The development of somatostatin analogues labelled with gallium-68 for PET studies of neuroendocrine tumours has also tended to limit the use of 18F-DOPA in oncology to medullary thyroid cancer and pheochromocytomas, due to their variable expression of somatostatin receptors. 18 F-DOPA has also an established role in neurology. LDOPA (L-dihydroxyphenylalanine) is the immediate precursor of dopamine, a neurotransmitter in the CNS predominantly found in the nigrostriatal region, and defects in this region are strongly related to neurodegenerative and movement disorders. Although dopamine in the circulation does not cross the bloodebrain barrier, L-DOPA is carried into the brain by the large neutral amino acid transport system, converted into dopamine by the action of Laromatic amino acid decarboxylase, and then stored in intraneuronal vesicles, from which it is released when the nerve cell fires. Because 18F-DOPA is an analogue of L-DOPA, this positron-emitting compound is used clinically to trace the dopaminergic pathway and to evaluate striatal dopaminergic presynaptic function. PD is a slowly progressive disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. In the early phase of disease, clinical signs may be subtle or can be confused with other movement disorders. Furthermore, the clinical diagnosis can be influenced and complicated by symptomatic medication. Considering these factors, in vivo markers of dopaminergic degeneration are important for the early diagnosis and monitoring of disease progression, and neuroimaging procedures (for example, 18F-DOPA PET and 123IN-(3-fluoropropyl)-2b-carbomethoxy-3b-(4-iodophenyl) nortropane [FP-CIT] SPECT for the presynaptic dopaminergic system) can help clinicians in selected cases. Objective in vivo markers of dopaminergic degeneration are therefore important for the early diagnosis and monitoring of disease progression, and neuroimaging procedures (like 18F-DOPA PET and FP-CIT SPECT for the pre-synaptic dopaminergic system) can be of value to clinicians in selected cases. Although 18F-DOPA is infrequently used in the clinical setting compared to FP-CIT, because of the need of a cyclotron-based radiopharmacy and the relatively complicated synthesis,58 its accuracy has been shown to be similar to that of FP-CIT, and it correlates reasonably well with motor scores and disease duration.59 18F-DOPA and FPCIT, in fact, demonstrate two different aspects of the presynaptic dopaminergic system d the first reflecting the activity of the decarboxylating enzyme and the storage capacity of dopamine,60,61 the latter reflecting the activity of the transmembrane dopamine transporter (DAT).62 This probably accounts for discordant results in the literature when the two compounds are directly compared in this clinical context. In the early phases of PD the decarboxylating enzyme can be up-regulated as a compensatory phenomenon, and the uptake of 18F-DOPA may, therefore, be normal, even in patients who have PD. Conversely, DAT is down-regulated, and this makes FP-CIT SPECT more sensitive for the early detection of PD.63 For the monitoring of disease progression, the two compounds are theoretically equivalent, and F-DOPA, despite significantly higher costs, may present advantages over FP-CIT in terms of length of the procedure and image quality. 68 Ga-DOTA-somatostatin receptor analogue As 111In-pentetreotide has proven high sensitivity for the detection of neuroendocrine tumours (NETs) and treatment C. Nanni et al. / Clinical Radiology 65 (2010) 536e548 541 Figure 4 A patient with an ileal NET. 18F-DOPA PET/CT was used to identify widespread disease by visualizing several, previously unknown, small lesions [(a) vertebral lesion, (b) mediastinal node and rib lesion, (c) hepatic lesion, (d) scapular lesion, (e) and (f) soft-tissue lesions, (g) bone medullary lesion]. with somatostatin analogues is of proven efficacy, the next step is to use radiolabelled somatostatin analogues for metabolic radiotherapy in inoperable patients. 90Y-DOTATOC (1,4,7,10-tetraazacyclododecane-N,N0 ,N00 ,N000 -tetraacetic acid, Tyroctreotide) and 177Lu-DOTA-TOC are therapeutic compounds that have been used for NET treatment with encouraging results, the best returning a response rate of 33%. 111In-DTPA-octreotide (Octreoscan) is the diagnostic agent classically used in the preliminary phase to assess the biodistribution of the therapeutic compound, based on binding to the sst2 receptor subtype. For PET studies, 68GaDOTA-TOC has been used as the positron-emitter tracer.64 Recently, 68Ga-DOTA-NOC (tetraazacyclododecanetetraacetic acid-[1-Nal3]-octreotide) has been synthesised by Wild and co-workers.65 This compound for PET imaging has high affinity for sst2 and sst5 receptors and has been used for the detection of NETs in preliminary studies. As in the case of 111In-octreotide, the uptake of 68Ga-DOTA-NOC is based on a receptor mechanism and, although this has not yet been adequately assessed, it seems to have higher sensitivity for NETs (Fig. 5). Furthermore, it has several advantages over 111In-octreotide for both the patient and the physician: increased spatial resolution, the possibility of performing whole-body tomographic studies with a short uptake time (60 min), relatively easy synthesis and the possibility of using hybrid PET/CT systems, thereby increasing diagnostic accuracy.65e67 As 68Ga-DOTA-NOC binds to NETs via a receptor mechanism, the sensitivity of this compound could be lower than that of 18F-DOPA, which accumulates via a metabolic mechanism, in some histological types expressing a low number of somatostatin receptors. Conversely, 68Ga-DOTA-NOC PET is likely to be of higher value prior to metabolic radiotherapy in order to assess the biodistribution of the therapeutic compound. However, to date, no studies have been published on this issue. The overall sensitivity and specificity of 68Ga-DOTANOC as compared to those of 18F-DOPA have still to be definitely assessed. In the paper by Ambrosini et al., a series of 13 patients affected by NETs was imaged using both 18 F-DOPA PET/CT and 68Ga-DOTANOC PET/CT. A higher detection rate was noted with DOTANOC (13/13 patients versus 9/13 patients) but larger series of patients are required to define the circumstances that favour one tracer over the other.68 Another point that remains unclear is the relative sensitivity of the available somatostatin analogues. Several compounds have been synthesized, but for ethical reasons related to radiation dose, it is not possible to try different compounds in the same patient. Briefly, the available compounds include indium, gallium, yttrium, and lutetiumlabelled molecules (DOTA-NOC, DOTA-TOC, DOTA-TATE, DOTA-BOC, DOTA-NOC-ATE, DOTA-BOC-ATE, DOTA-OC). Their affinity for different subtypes of the somatostatin receptor was assessed, and the most interesting molecule 542 C. Nanni et al. / Clinical Radiology 65 (2010) 536e548 Figure 5 A patient with a pancreatic neuroendocrine tumour. Restaging 18F-DOPA PET/CT (a) compared with 68Ga-DOTANOC PET/CT (b). Although both procedures were positive, indicating multiple localizations, 68Ga-DOTANOC PET/CT identified more liver lesions showing a higher sensitivity. seems to be 68Ga-DOTA-NOC. In the same paper 68 Ga-DOTA-NOC and 68Ga-DOTA-TATE were tested in patients, and the former showed more small secondary lesions than the latter. However, no definitive results are available so far.69 11 C-acetate 11 C-acetate is a PET tracer that accumulates as an intermediate molecule both in the glucose catabolism pathways and in membrane metabolism, partially resembling FDG and choline in its behaviour. Acetate can be transformed into acetyl-CoA, entering the tricarboxylic acid cycle or used as a precursor for membrane fatty acids. As with 18F-DOPA, the original application of 11C-acetate was not in oncology but in cardiology, due to its accumulation in the myocardium in parallel with fatty acid oxidation, making it useful in the evaluation of cardiac energy metabolism. Regarding oncology, 11C-acetate was first used as a choline analogue for the evaluation of prostate cancer, showing a similar sensitivity and specificity.70 More recently, Delbeke et al. used 11C-acetate and 18 F-FDG for the evaluation of liver masses. Preliminary results demonstrate that 11C-acetate has better sensitivity for low grade as opposed to high-grade hepatic neoplasms, while FDG exhibits the opposite behaviour, being insensitive for low-grade cancer types that are differentiated and still produce a cytoplasmatic de-phosphorylase (this enzyme de-phosphorylates the intra-cytoplasmatic tracer allowing it to pass out of the cell, reducing the overall PET sensitivity) and very sensitive for high-grade tumours (de-differentiated). The two radiotracers may, therefore, have a complementary role in hepatic cancer 71, 72 (Fig. 6). 18 F-FLT [18F]FLT (3-deoxy-3-fluorothymidine) is a thymidine analogue that follows the salvage pathway of DNA synthesis, but is not incorporated into the DNA molecule. The halogen substitution in the 30 position of [18F]FLT results in a decreased affinity for the pyrimidine transporter as compared with thymidine. Moreover, the affinity of [18F]FLT for thymidine kinase 1 (TK1) is reported to be 30% lower than the affinity of thymidine. Both mechanisms lead to a preferential uptake and phosphorylation of thymidine, which may explain the low [18F]FLT uptake in tumour cells compared to thymidine. In addition, [18F]FLT is phosphorylated by TK1 into [18F]FLT-monophosphate, after which it is trapped in the cell. This phosphorylation by TK1 forms the basis for the use of [18F]FLT as a proliferation tracer, as intracellular trapping of [18F]FLT is increased in malignant cells. Consequently, uptake of the radiopharmaceutical is C. Nanni et al. / Clinical Radiology 65 (2010) 536e548 correlated with cellular proliferation, making it useful in detecting tumours, differentiating between malignant and benign lesions, measuring tumour aggressiveness, and monitoring response to treatment. Uptake is rapid and tumours can be visualized 45e60 min after administration of 300 MBq. Within the cell, [18F]FLT can be found predominantly in its phosphorylated form, with only a negligible amount incorporated into DNA. The PET signal reflects uptake of [18F]FLT as a function of nucleoside transport and consecutive activation of intracellular thymidine by monophosphorylation. [18F]FLT is rapidly excreted by kidneys in non-metabolized form. Physiological uptake of [18F]FLT is seen in bone marrow, liver, and the urinary tract. In untreated patients, variable uptake of FLT in the spleen can be observed. Normal tissues exhibiting rapid turnover also usually show increased uptake of [18F]FLT. In contrast to [18F]FDG-PET, no uptake is seen in the brain, skeletal muscles, or myocardium, but 543 moderately increased uptake can be seen in the liver due to glucuronidation of [18F]FLT. Tumours within any of these tissues normally showing high uptake, especially lesions with a low proliferation fraction, may therefore be missed. Also, variable uptake can be seen in normal gut, and so for suspected tumours of the gastrointestinal tract, an alternative examination such as as [18F]FDG PET is indicated. When [18F]FLT PET is repeated some days after high-dose chemotherapy, uptake in bone marrow and spleen can be markedly reduced or completely absent, and the same is true of tumour tissue if the therapy is effective. As mentioned earlier, there is a high correlation between [18F]FLT uptake and proliferative activity of tumours, and benign lesions do not show significant focal concentration. Areas of focal increased FLT uptake can generally be considered as positive for tumour presence, with the proviso that malignant lesions with low proliferation fraction may not be visualized. As with [18F]FDG PET, the evaluation of Figure 6 A patient with hepatocarcinoma. 11C-acetate PET/CT (a) demonstrated a liver focal area consisting with cancer. Correspondent 18F-FDG image (b) is falsely negative. 544 C. Nanni et al. / Clinical Radiology 65 (2010) 536e548 tracer uptake is calculated as standardized uptake values (SUV). An initial baseline [18F]FLT PET-CT scan is performed before any specific treatment and, where possible, compared with other conventional staging examinations (clinical data, laboratory data, CT, MRI, scintigraphy). The timing of repeat scans is determined by the tumour type, the degree of proliferative activity, and the type of treatment being used. For example, in lymphoma, the second examination is performed at day 6 or 7 after the beginning of therapy. Experience with [18F]FDG-PET has been obtained in a number of different tumours. Differentiating malignant from benign solitary pulmonary nodes is a frequent diagnostic problem. [18F]FDG-PET exhibits excellent sensitivity and good specificity in this context, but false positives mainly due to granulomatous and inflammatory disease are a problem. Therefore, a more specific tracer as [18F]FLT that does not show uptake in inflammatory tissues and benign tumours might be useful. [18F]FLT is effective in detecting primary non-small cell lung cancer (NSCLC), but in the detection of lymph node metastases or distant metastases its performance is unacceptable in comparison with [18F] FDG PET. [18F]FLT PET in colorectal cancer shows good visualization of primary tumour, lung metastases and peritoneal lesions. However, the high background uptake in liver makes [18F]FLT PET unsuitable for the detection of hepatic metastatic disease. Possible indications for [18F]FLT-PET are non-invasive evaluation of tumour grade and measurement of early response to therapy. Better performance of [18F]FLT PET has been described in haematological neoplasms. In particular, lymphoma involving the thorax or the brain can be detected more sensitively than with standard imaging methods, presumably due to the lower background activity of [18F]FLT. A significant correlation between proliferation fraction and [18F]FLT uptake can be demonstrated in lymphoma, with uptake being significantly higher in aggressive types. Using a cut-off value for [18F]FLT SUV ¼ 3, [18F]FLT-PET accurately differentiates between aggressive and indolent lymphoma, which can be of clinical relevance in CNS lymphoma. The application of [18F]FLT imaging in pancreatic cancer is not well studied yet, but as it has a higher specificity compared to [18F]FDG, further evaluation of [18F]FLT PET regarding differential diagnosis and management of patients with pancreatic masses is recommended. [18F]FLT PET in gastric cancer has a higher sensitivity compared with [18F]FDG, especially for signet ring cell cancers. This histological subtype is frequently associated with negative [18F] FDG PET, so [18F]FLT may have a clinical role. Few data are currently available on the visualization of breast cancer with [18F]FLT PET, and its role is not clear. Physiological uptake in bone marrow and liver will hamper the detection of bone and liver metastases. The sensitivity for detection of axillary lymph node metastases has not yet been evaluated, but with sentinel lymph node biopsies even micrometastases can be found. Measuring the early response to neoadjuvant chemotherapy for locally advanced breast cancer is probably the most interesting topic for future research in this area. Conventional imaging techniques provide excellent anatomical images of the brain. In the management of brain tumours, PET could provide information on the tumour grade and help in assessing the optimal site for biopsy. PET could also assist in the evaluation of response to therapy. Unlike [18F]FDG, [18F]FLT background uptake in normal brain tissue is low, probably owing to the slow proliferation rate of normal brain tissue. [18F]FLT-PET therefore offers images with excellent contrast between tumour tissue and normal brain, and future research will have to answer the question of whether [18F]FLT-PET can differentiate between benign and malignant tissue and between residual tumour and radionecrosis. If [18F]FLT proves to be a sensitive and specific tracer in this context, it may be very useful (in combination with CT or MRI) for establishing the best site for tumour biopsy or for planning of radiotherapy in a heterogeneous tumour. Finally, it has been shown that [18F]FLT PET is able to differentiate between low-grade and high-grade soft tissue sarcomas and could, therefore, non-invasively predict which patients could benefit from hyperthermic isolated limb perfusion (HILP). In conclusion, [18F]FLT can be seen as a proliferation tracer because it is phosphorylated by TK1. The activity of TK1 is generally higher in malignant cells and therefore [18F]FLT is probably more tumour-specific than many other PET tracers. There are also strong correlations between [18F] FLT uptake and histopathological proliferation markers (Ki67). As [18F]FLT PET is able to visualize and quantify the proliferation rate of tumours, it can serve as a non-invasive tool for establishing tumour grade. Furthermore, [18F]FLT PET can visualize the heterogeneity within tumours. In combination with CT or MRI, [18F]FLT can help define the optimum site for biopsy in these tumours (for example in brain tumours). Additionally, as no uptake is expected in inflammatory cells, another indication can be the evaluation and measurement of the response to anti-cancer therapy. Non-responders could be detected earlier and they could be switched to second-line treatment, and [18F]FLT PET represents a highly promising method contributing to the individualization of cancer therapy. But, as mentioned earlier, there are some difficulties with [18F]FLT: for example, the low overall uptake in some tumours, the changes in uptake after anti-tumour therapy, and the indirect mechanism of visualizing proliferation. If in the future these problems can be overcome, it will be possible to establish the role of [18F]FLT in PET imaging oncology.73e80 18 F-fluoride 18F-fluoride is a PET tracer that can be used for bone imaging, relying on the same mechanism of uptake as other bone-seeking agents in conventional nuclear medicine. Tracer uptake depends on regional blood flow and, in particular, on local osteoblastic activity. Although only a few studies comparing 18F fluoride PETeCT and bone scan with 99mTcemethylene diphosphonate (MDP) exist, 18F fluoride PETeCT seems to be the more sensitive technique for the evaluation of bone metastases. Moreover, the specificity is C. Nanni et al. / Clinical Radiology 65 (2010) 536e548 increased due to the precise anatomic correlation with CT allowing the clarification of non-specific benign lesions. According to recent literature 18F-fluoride may be useful especially in patients affected by prostate cancer due to the high probability of blastic bone metastasis. Fluoride seems to be more sensitive than choline for diagnosing secondary blastic bone lesions, but it can be falsely positive in benign conditions like osteophytes or fractures, which are usually negative on choline imaging.81 Other tracers A number of tracers showing affinity for processes other than metabolism have been introduced, or are under investigation. Hypoxia Compounds such as 18F-misonidazole, 64Cu-ATSM, 18FEF5, which highlight the presence of hypoxic areas within large tumours, are useful for patients undergoing radiotherapy. It is well known that hypoxia is one the most important factors associated with treatment resistance, and hypoxic areas can be identified and over-treated compared to non-hypoxic malignant tissues.82 Perfusion Tissue perfusion is another parameter to which PET techniques are being applied. 13N-ammonia and rubidium82 are used to evaluate myocardial perfusion, although the technique has not been widely-employed, largely due to the accuracy and availability of conventional myocardial SPECT. Their short half-lives (10 min for ammonia and 2 min for rubidium) pose logistic difficulties, and PET centres dedicated to cardiology are required to fully exploit their potential.83, 84 Other vailable perfusion tracers are 13Nammonia and 15OH2O, and their use is already standard for human studies.85 Another possible way of assessing myocardial perfusion is to use 11C-acetate with dynamic acquisition, as the myocardial blood flow measured with 15OH2O and with acetate are directly correlated. Acetate has several advantages over other tracers, such as easy synthesis and a more suitable half-life.86 Angiogenesis This process leads to the formation of new capillaries by cellular outgrowth from existing microvessels. It occurs as part of the natural healing process after ischaemic injury and includes local proliferation and migration of vascular smooth muscle and endothelial cells to form new capillaries. Many factors such as tissue ischaemia and hypoxia, inflammation, and shear stress can stimulate angiogenesis, mediated by circulating angiogenic factors, which include vascular endothelial growth factor (VEGF), angiopoietins, basic fibroblast growth factor, transforming growth factor, extracellular matrix, and integrins (the most important being avb3). Approaches for the targeted imaging of angiogenesis include evaluation of the altered expression of VEGF receptors and avb3 integrins.87 VEGF receptors can be considered as targets for imaging of mediators of 545 ischaemia-induced angiogenesis, using VEGF121 as the targeting ligand. 64Cu-DOTA-VEGF121 for small animal PET studies was recently synthesized and tested in vivo with successful results in mice tumour models. Another way to image angiogenesis is based on avb3. The avb3 integrin is a protein expressed in angiogenic vessels and mediates intercellular adhesion of proteins with the exposed arginine-glycine-aspartic (RGD) tripeptide sequence. Haubner and co-workers reported the synthesis of cyclic RGD peptides that can be labelled with 18F-galacto and 64Cu-DOTA for PET studies.88 The value of the avb3 targeted imaging approach for assessment of myocardial angiogenesis was recently confirmed, even though most studies have been based on single photon emitter labelled compounds. It was shownthat these tracers bind to myocardial ischaemic areas showing reduced sestamibi uptake. Apoptosis. Apoptosis, or programmed cell death, occurs in association with many cardiovascular diseases. Cells undergoing apoptosis express on their cell membrane phosphatidylserine, which is a favourable target for imaging of apoptotic processes.85 Annexin-V is a mediumsized physiological human protein with a high Ca2þdependent affinity for the phosphatidylserine on the outer leaflet of the cell membrane. Annexin-V can be labelled with a radionuclide and used in apoptosis imaging. Although 99mTc-labelled annexin-V is now available for imaging cardiac apoptosis in vivo in clinical practice (to detect small infarctions undetectable with sestamibi and to monitor the heart transplant rejection process), the positron emitter labelled compound (124I-annexin-V) has to date been tested only in an animal model of hepatic apoptosis and not on cardiac infarction.89 Reporter genes. In recent years, the use of reporter genes to monitor gene expression has helped in advancing the understanding of many biological processes. The introduction of a reporter gene into the DNA of a specific cell that must be tracked in vivo leads to the production of a specific reporter protein that can then become the specific target for a PET probe. In this way, subject to the stability of the reporter gene, it is possible to detect the viability and location of the genetically marked cells over a long period (up to months). The most common approach for PET studies involves the use of 18F-fluoro-3 hydroxymethylbutyl guanine (FHBG) as a reporter probe for imaging of the enzyme-based reporter gene herpes simplex virus type 1 thymidine kinase (HSV1-tk) and its mutant derivative, HSV1-sr39tk.90 For cardiac applications, the importance of the reporter geneereporter probe technique derives from the idea of treating cardiac infarction with stem cells in order to prevent the left ventricle from remodelling. After initial disappointment, it was found that the association of stem cells with specific growth factors inducing their differentiation into myocytes gives good results in terms of viability and contractility recovery; however, for definitive assessment it would be necessary to ascertain in vivo the cell survival, final location and function. Unfortunately none of these tracers have been injected into human patients yet, 546 C. Nanni et al. / Clinical Radiology 65 (2010) 536e548 and all the possible applications are limited to animal models of cancer or of cardiac infarction. 18 F-ethyl-tyrosine (FET). FET, a recently introduced amino acid PET tracer for the diagnosis of brain tumours, has been shown to exhibit a similar diagnostic potential to MET, with tumour delineation appearing to be identical. FET has been shown to reliably differentiate tumour recurrence from reactive changes following various therapies, particularly external radiation therapy.91, 92 Studies have shown that MET-PET and FET-PET have similar accuracies in diagnosing gliomas.93 Furthermore, FET-PET has been shown to have value in the prognosis and evaluation of treatment in patients with gliomas.94, 95 Tumour specificity has been the major reason for the interest generated in this tracer, particularly in the setting of cerebral glioma. In one study 94 the added value of FET-PET was investigated in 31 patients with suspected gliomas. PET and MR imaging were coregistered and 52 neuronavigated tissue biopsies were taken from lesions with abnormal MR imaging signal and increased FET uptake (match), as well as from areas with abnormal MR imaging signal but normal FET or vice versa (mismatch). Combined use of MR imaging and FET-PET yielded a sensitivity of 93% and a specificity of 94%. The investigators concluded that combined use of MR imaging and FET-PET significantly improves the identification of tumour tissue. In a comparative study between MR imaging, FET-PET, and MR spectroscopy96 the predictive value of each modality was compared in 50 patients with suspected gliomas. The diagnostic accuracy in differentiating neoplastic from non-neoplastic tissue increased from 68% with MR imaging alone to 97% with MR imaging used in conjunction with FET/PET and MR imaging spectroscopy. Sensitivity and specificity for tumour detection were 100% and 81% for MR spectroscopy, and 80% and 88% for FET-PET, respectively. Conclusion Approximately 90% of PET examinations in oncology, cardiology, and neurology currently employ FDG. However, there are several indications where FDG is not useful; in particular, prostate cancer, liver cancer, CNS tumours, and NETs. Other tracers, labelled either with 11C or 18F, have been synthesized and tested for the types of malignant tumours that where FDG is unhelpful. These radiotracers are specific for tumours with a relatively low incidence and for which there is no established diagnostic algorithm. Some of these tracers are difficult to prepare and some are labelled with short half-life isotopes, requiring a cyclotronequipped PET centre. For this reason, many of the newer tracers are not yet in routine use, but these compounds are important and will grow in number and application. This should ensure that in the future we have available a wide range of compounds targeting different tumours and physiological and pathological processes. 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