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F-Thymidine

LauraTravascio, FedericoPadovano, MarziaColandrea, MarioLeporace, LucaFrontino, BhagwantRaiMittal, FerdinandoCalabria, andRakheeVatsa

Abbreviations

HGG High grade glioma HPLC High-performance liquid

C-MET

F-DOPA

F-FDG

F-FLT 3′-deoxy-3’-18F-uorothymidine ADC Apparent diffuse coefcient BBB Blood–brain barrier BCBM Breast cancer bone metastases BM Bone marrow CE-CT Contrast enhanced computed

CT Computed tomography DTI Diffusion tensor imaging FLAIR Fluid-attenuated inversion

FNAC Fine needle aspiration cytology Gd Gadolinium

C-Methionine

F-Fluorodiidrossiphenilalanine

F-Fluorodeoxyglucose

tomography

recovery

chromatography LGG Low grade glioma MIP Maximum intensity projection MRS MR spectroscopy OSEM Ordered subsets expectation

maximisation PDL1 Programmed death ligand 1 PET Positron emission tomography PET/CT Positron emission tomography/

computed tomography PET/MRI Positron emission tomography/

magnetic resonance imaging PWI Perfusion weighted imaging RUL Right upper lobe STIR Short tau inversion recovery SUVmax Maximum standardised uptake

value

The authors declare they have obtained permission for any previously published material used in their chapter.

L. Travascio (*) · L. Frontino UOC Nuclear Medicine, P.O.Pescara Santo Spirito, Pescara, Italy

F. Padovano UOSD Nuclear Medicine, Teramo, Italy

M. Colandrea Division of Nuclear Medicine, IEO European Institute of Oncology IRCCS, Milan, Italy

M. Leporace Department of Nuclear Medicine and Theragnostics, Mariano Santo Hospital, Cosenza, Italy

https://doi.org/10.1007/978-3-031-54196-4_18

SUVmean

Mean standardised uptake value

SUVpeak Peak standardised uptake value

B. R. Mittal Department of Nuclear Medicine at Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

F. Calabria Department of Nuclear Medicine and Theranostics, Mariano Santo Hospital, Cosenza, Italy

R. Vatsa Department of Nuclear Medicine, ACTREC, Tata Memorial Centre, DAE0, Navi-Mumbai, India

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SWI Susceptibility weighted imaging TBR Tumour-to-blood ratio TDPK Thymidine diphosphate kinase TK-1 Thymidine kinase 1 TMPK Thymidine monophosphate

kinase

WB-DWIBS Whole-body diffusion-weighted

imaging with background body signal suppression

raphy (PET) radiotracer for invivo imaging of tumour proliferation [2]. 18F-FLT has been synthesised via type 2 nucleophilic substitution reaction-based two-step method reported by Grierson and Shields [3]. High-performance liquid chromatography (HPLC) became the predominant method for the purication of the end product. The long synthesis time (~100min) and less end-of-synthesis yield (7%) lead to further modication in the synthesis process. Currently, 18F-FLT is predominantly synthesised using 3-N-Boc-5′-O-dimetoxytrityl-3′-O-

18.1 Synthesis

nosyl- thymidine (N-Boc-thymidine) as the precursor molecule by a three-step method

3′-Fluoro-3′-deoxythymidine (FLT), also known as alovudine, is a thymidine analogue introduced initially as a candidate to target the human immunodeciency virus [1]. Fluorine-18 (18F) tagged deoxythymidine, or 3′-deoxy-3′- [18F]uorothymidine (18F-FLT) (Fig.18.1), has been developed as a positron emission tomog-

(Fig.18.2) in cassette-based automated synthesis module [4]. The labelling reaction is carried out by incubating the N-Boc-thymidine precursor with uorine- 18 at 100°C or 130°C in the presence of a phase transfer catalyst under an anhydrous environment. During the second step, the uorinated precursor undergoes hydrolysis in the presence of hydrochloric acid (HCl) at a reduced temperature (85°C) to remove the protecting groups. At last, the nal product (18F-FLT) is puried using a combination of cartridges (PS-H+, WAX, HLB, and alumina) based on the solid phase extraction method. The neutralised hydrolysed mixture (with NaOH) is passed through the combination of cartridges to remove various cationic, strong acid, non-polar, and inorganic impurities. After elution from the cartridge, the nal product is

Fig. 18.1 Structure of (a) thymidine and (b) 3′-deoxy-3′-

F]uorothymidine (18F-FLT)

[

passed through a 0.22μm lter before collecting in the mother vial [

5–7].

Fig. 18.2 Schematic diagram showing the steps involved in synthesis of sor molecule via nucleophilic substitution reaction followed by hydrolysis and purication by solid phase extraction method (Ns nitrobenzenesulfonyl [nosyl leav-

F-FLT using N-Boc thymidine as precur-

ing group], DMTr dimethoxytrityl and Boc tertbutyloxycarbonyl [protecting group], ACN acetonitrile, TBA tetrabutyl ammonium salt, Byproducts unreacted uorine-18, thymine, thymidine, chlorothymidine, stavu-

F-Fluoronosyl, SPE solid phase extraction)

dine,

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18.2 Pharmacokinetics

F-FLT, a thymidine analogue, targets the thymidine salvage pathway, a process by which DNA precursors are supplied to the dividing cells. 18FFLT is transported into the cells from the blood via active transport through nucleoside transporters and sodium-dependent carriers (Fig. 18.3). However, the nucleoside transporter pathway is considered the prominent pathway in tumour cells [8–10]. The 18F-FLT is subsequently phosphorylated to 18F-FLT-monophosphate (18F-FLTMP) by thymidine kinase 1 (TK-1), a cytosolic enzyme overexpressed during the S-phase of the cell cycle. The presence of 18F in place of the hydroxyl group at 3′ position hinders

F-FLT from following the biochemical pathway similar to thymidine. The 18F-FLTMP, being a negatively charged molecule, remains trapped inside the cell instead of getting incorporated into the DNA [10–13]. 18F-FLT is a surrogate to determine the cell proliferation index by measuring the TK1 activity.

Unlike thymidine, 18F-FLT is resistant to the action of thymidine phosphorylase (TP) and remains remarkably intact in the body. The nondegraded 18F-FLT is cleared via kidneys and

excreted by the urinary tract. However, 18F-FLT also undergoes glucuronidation (~one-third of administered dose at 1 h) by glucuronyltransferase resulting in the accumulation of metabolites in the liver [10, 14–17]. Certain adverse effects like peripheral neuropathy and hepatic toxicity have been reported for therapeutic doses of FLT used to treat the human immunodeciency virus. However, during PET imaging, only 5–10mCi of 18F-FLT is administered, containing only a trace amount (micrograms) of FLT. No such adverse reactions have been reported in the literature for PET/CT imaging [18, 19].

18.3 Physiological Distribution

F-uorothymidine (18F-FLT), an F18-labelled analogue of thymidine, is the only nucleoside incorporated in DNA, but not in RNA, which makes it appealing as a biomarker of DNA synthesis and cellular proliferation [20, 21]. As previously described in the pharmacokinesis paragraph, 18F-FLT enters cells both passively and actively, is phosphorylated by thymidine kinase 1 and trapped, though not being incorpo-

Fig. 18.3 Schematic diagram showing cellular uptake mechanism and retention of thymidine and salvage pathway. Both thymidine and cell by nucleoside transporters (NT), followed by phosphorylation by thymidine kinase 1 (TK1). Further phos-

F-FLT via

F-FLT enter the

phorylation is carried out by thymidine monophosphate kinase (TMPK) and thymidine diphosphate kinase (TDPK). The phosphorylated thymidine gets assimilated in the DNA.However, phosphorylated incompatible substrate remains trapped inside the cell

F-FLT being an

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rated in DNA.Therefore, TK1, expressed during DNA synthesis, is the key enzyme responsible for intracellular trapping of 18F-FLT [22].

Physiological uptake of the tracer is seen in the liver, due to glucuronidation of 18F-FLT (SUVmean at 60min post-injection being 12.2), in proliferating bone marrow, especially in the skull and cervical tract of the spine, and urinary tract, as it is cleared via the kidneys [23]. No uptake is seen in skeletal muscles and myocardium at 45minutes after i.v. injection. In fact, increased physiologic uptake can be seen in earlier imaging, due to blood pool and muscle activity of the left ventricle, rapidly washed out. Variable uptake is seen in normal gut, due to mucosa cells rapidly proliferating. At 60′ after injection, uptake is low in head and neck region, lung and kidney parenchyma, and pelvic organs. 18F-FLT uptake in the brain does not depend on any transporter, but it requires the blood–brain barrier (BBB) to be disrupted [23–25]. Except bone marrow, which uptake changes from the newborn to the elderly, physiologic ageing does not affect 18F-FLT uptake.

Cysouw et al. [26] evaluated 90 treatment naïve oncological patients in order to quantitatively investigate normal reference uptake of blood pool, lung, liver, and bone marrow, either by static or frames of dynamic acquisition, respectively, 60 min and 45–65 min postinjection. No signicant difference was found in static versus dynamic acquisition protocols, and SUVmax was as valuable as SUVpeak in estimating tissue

F-FLT uptake. Liver and bone marrow SUVmax were highly repeatable and suitable for image-based quality control.

18.4 Clinical Indications

Several kind of tumours have been studied, to date, by 18F-FLT PET imaging with staging and restaging purpose, eventually compared to 18FFDG or 18F-DOPA, as 18F-thymidine uptake occurs in proliferating tissues and less likely accumulates in areas of inammation associated with cancer therapy. Despite being a promising radiopharmaceutical agent, 18F-FLT is yet con-

sidered unconventional and is not routinely employed in clinical setting.

Herein is a brief overview of oncological and

non-oncological indications for

F-FLT PET.

18.4.1 Oncological Indications

F-FLT was shown promising in primary breast cancer evaluation, due to high contrast between primary tumours or metastases and surrounding tissue in most cases [27, 28], and somehow also in early predicting response to chemotherapy [29–31], especially when correlated signicantly to ki67 tissue levels at baseline and after chemotherapy [29, 32–35]. When studying 6 naïve invasive ductal breast cancer patients, Mori etal. [28] found 18F-FLT-SUVmax in breast lesions and axillary lymph nodes correlated to 18F-FDGSUVmax, with SUVmax of 18F-FLT approximately half that of 18F-FDG, but bone metastases demonstrated lower accumulation than bone marrow in 18F-FLT scans. In particular, lymph nodes with higher 18F-FLT accumulation may have faster cancer cell proliferation, possibly distinguishing between inammation and physiological accumulation.

Kostakoglu etal. [33] recruited 43 pts. with primary breast cancer to evaluate 18F-FLT-PET to predict pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC). Eight/43 patients reached pCR, and ΔSUVmax between

F-FLT-PET before and after NAC signicantly correlated to pCR. In this report, anyway, SUVmax and Ki67 showed a weak correlation before NAC, on biopsy specimens, and better correlation after NAC, as measured on surgical specimens.

Kenny etal. [29] evaluated 13 patients with

F-FLT-PET 1week after chemotherapy (5- uor ouracil- epirubicin-epirubicin) and found signicant changes in breast cancer proliferation, measured either by SUV and Ki67, in responding lesions versus non-responding ones. Pio et al. [30] examined side-by-side 18F-FDG and 18F-FLT imaging in 14 pts. with newly diagnosed breast cancer or metastatic breast cancer before, 2 weeks after the rst cycle, and at the end of a new

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pharmacologic treatment. They reported that a mean change in 18F-FLT uptake in primary and metastatic breast cancer after one cycle signicantly correlated to late changes in tumour size (seen at CT) and in CA27.29 level. Contractor etal. [31] found early 18F-FLT decrease uptake (SUVmax at 60 min), i.e., after one cycle of docetaxel treatment, in 20 patients with stage II– IV breast cancer unresponsive to rst-line chemotherapy or progressing on previous therapy. In the studies above, a decrease in 18F-FLT uptake early after treatment was correlated to better late response. This decrease is interpreted as a decrease in proliferation rate and demand of thymidine. However, treatment with drugs interfering with endogenous thymidine synthesis (e.g., 5-uorouracil) may result in a are of 18F-FLT uptake due to an increase in TK1 activity [11]. Despite a lesser uptake in inammatory tissues,

F-FLT routine use in breast cancer evaluation was limited because of its high physiologic uptake in liver and bone marrow (Fig. 18.4), which are preferential sites for breast cancer metastases. In fact, Su et al. [36] evaluated

F-FLT-PET impact in 25 metastatic breast can-

cer patients after 2 chemotherapy cycles, compared to 18F-FDG-PET.While 18F-FLT-PET was not predictive of response to therapy nor OS,

F-FDG-PET was. The patients’ population consisted of 25 patients with metastatic breast cancer mainly with osseous and liver metastases (16/25 bony, 6/25 liver, 8/25 lung, 8/25 lymph node, 7/25 other) that displayed a low target-tobackground ratio, possibly responsible for this study nding.

A few authors, however, reported 18F-FLT- PET accuracy in breast cancer brain metastases (BCBM). Morikawa etal. [37] explored 18F-FLTPET as a complementary imaging tool in a correlative study conducted within a phase I trial in 15 patients with BCBM treated with sorafenib and whole brain radiotherapy versus whole brain radiotherapy alone. In total, 57 lesions were studied by brain 18F-FLT-PET. 18F-FLT uptake of brain lesione changed early, suggesting a timing antiproliferative effect with both regimens in responder patients. A similar result was found by O’Sullivan etal. [38], who showed the impact of ANG1005—a drug conjugate consisting of paclitaxel covalently linked to Angiopep-2, designed to cross the blood–

Fig. 18.4 A 50-year-old woman with lump in left breast for 10months associated with pain and axillary swelling with left BIRADS 5 and right BIRADS 2 on mammography and biopsy proven IDC, grade III underwent PET/CT (a–e) for disease evaluation. The maximum intensity projection (MIP) image (a) showed physiological uptake of tracer in bone marrow and liver with excre-

F-FLT

tion through urinary bladder along with abnormal tracer uptake in the thoracic region. This uptake on fused transaxial PET/CT and CT images (b–e) localised to left breast mass (~5.4 × 4.8 × 6.0 cm, SUVmax 7.9) (b, d) with enlarged multiple left level I axillary lymph nodes (~2.6×1.8cm, SUVmax 11.3) (c, e)

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brain barrier—on BCBM by means of brain

F-FLT-PET in 10 patients (29 target and 20 nontarget brain mets), moderately associated to MRI results. Both these authors also highlighted the advantage of low brain uptake of 18F- FLT and high uptake in brain lesions. A known limitation, though, is that benign lesions disrupting the blood– brain barrier (BBB) show 18F-FLT uptake similar to malignant tumours. Indeed, 18F-FLT-PET has been employed in malignant brain tumours imaging (Fig.18.5), whose uptake does not depend on any transporter but requires a disrupted BBB [39,

40]. Several authors reported 18F-FLT performance

in evaluating gliomas, better performing in high grade gliomas (HGG) than low grade (LGG) [41–43]. The rst question addressed to 18F-FLT concerned its ability to grade brain tumours, with a valuable performance differentiating grade II–IV gliomas [44] but, in case of intact BBB [45] or in case of BBB breakdown [46], tumours and benign lesions showed a similar scan.

Jacobs etal. [47] found a lower sensitivity for

F-FLT as compared to 11C-MET (i.e., 78% vs 91%) in 23 patients with histologically conrmed gliomas, especially in case of LGG. Also, semiquantitative parameters were signicantly lower in

F-FLT than 11C-MET (e.g., SUV 1.3 vs 3.1,

respectively, p<0.01). Several authors studied the impact of 18F-FLT on prognosis, and a recent systematic review by Guglielmo etal. [42] found 18FFLT uptake and texture parameters (skewness and kurtosis) to correlate to overall survival (OS, p=0.03 and p=0.02, respectively) in newly diagnosed glioma; also, patients who respond to therapy on 18F-FLT scan have shown longer OS.Differential diagnosis between tumour recurrence/pseudo-progression-radio-necrosis/pseudo-response is still challenging in brain neoplasms, and 18F-FLT change in SUVmax [48] did not discriminate between true progression and pseudo-progression as dened in MRI, but a lower SUVmax registered immediately after surgery and before treatment was correlated to better OS.Among others, images acquired according to kinetic scans [49, 50] better differentiated radiation necrosis to progression in gliomas, still in small population of patients.

Bashir etal. [51] have recently tested 18F-FLT capability to assess asymptomatic meningiomas progression and found tumour-to-blood-ratio (TBR) to predict progressive disease and, eventually, to guide to radicality instead of long-term monitoring.

Lung neoplasms also have been evaluated by

F-FLT-PET (Fig.18.6), in order to evaluate its

Fig. 18.5 A 38-year-old man with left cerebello-pontine medulloblastoma grade IV, post-chemoradiotherapy underwent regional residual disease evaluation. The abnormal foci of uptake in MIP (a) image is localised to heterogeneously enhanc-

F-FLT PET/CT for post-treatment

ing lesions in the periphery of left cerebellum (~1.5 × 1.8 cm, SUVmax—4.2) with mildly increased tracer uptake on PET only (b, e), fused PET/CT (c, f), and CT (d, g) images

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diagnostic accuracy compared to the mainly used

F-FDG, which can generate false positive and

false negative results. In Wang’s metanalysis [52],

F-FLT was signicantly less sensitive than 18FFDG for pulmonary malignancy detection (0.80 vs. 0.89, p<0.01) but was more specic compared to 18F-FDG in excluding benignities (0.82 vs. 0.66, p<0.01). Conversely, clinical impact on prognosis and therapy monitoring in lung cancer by 18F-FLT is being tested [53–55], early evaluating response to therapy and adding value when 18F-FDG-PET is positive or inconclusive. In fact, dual tracer evalu-

ation (18F-FDG and 18F-FLT) during chemo/radiotreatment seems to increase the global sensitivity of diagnosis of lung cancer relapse. An interesting application of 18F-FLT imaging in lung cancer during therapy with anti-PDL1 agents could be the early evaluation of response, discriminating from pseudo- progression [56], with longitudinal scans before and at 6weeks after treatment.

Noteworthy is 18F-FLT-PET possible impact in haematological disorders (Fig. 18.7), mainly in lymphomas [57, 58], with a better PPV and similar NPV than 18F-FDG-PET.

Fig. 18.6 A 62-year-old man with complaints of hemoptysis, cough, soft tissue mass in RUL with lymphadenopathy on CE-CT and FNAC proven NSCLC underwent

F-FLT PET/CT (a-g) for disease evaluation. The MIP

image (a) showed abnormal tracer uptake in the thorax

bcd

Fig. 18.7 A 50-year-old woman with complaints of weakness, leukopenia, thrombocytopenia, with BM biopsy proven hypoplastic marrow, underwent 18F-FLT PET/CT scan (a–g) for marrow evaluation. The maximum intensity projection (MIP) image showed increased tracer uptake at various points in axial and appendicular skele-

region which on fused PET/CT and CT images localised to tracer avid mass in RUL (~4.8×2.5×4.7cm, SUVmax

8.0) (b, e). Right mediastinal lymphadenopathy (precarinal-~1.1×1.7cm, SUVmax 9.2) (c, f) was also noted in fused PET/CT, CT and lung window (d, g) images

ton. On trans-axial fused PET/CT and CT images, the increased focal tracer uptake was localised to medial end of bilateral clavicles (SUVmax 16.1, left) (b, e), multiple sites in dorsolumbar vertebrae (SUVmax D12–10.9) (c, f), pelvis (SUVmax at right ala of sacrum—15.7) (d, g), and bilateral femora

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Fig. 18.8 A 31-year-old woman who is a known case of sarcoidosis underwent ation. The MIP image (a) showed abnormal uptake in the

F-FLT has been tested in several oncological

F-FLT PET/CT for disease evalu-

settings, such as gastrointestinal tract [59–62], head and neck neoplasms [63], and renal cell carcinoma, showing better specicity than 18F-FDG in T and N staging and better correlating to early response to treatment. However, because of its high uptake in marrow and liver, bony and hepatic metastases cannot be adequately assessed by 18F-FLT-PET.A limitation of 18F-FLT-PET studies is represented also by the paucity of each patients’ population.

18.4.1.1 Non-oncological Indications

A few studies report 18F-FLT performance in nononcological settings (Fig.18.8), i.e., not as a proliferation biomarker. In fact, 18F-FLT has been employed in evaluating bone marrow distribution in order to spare proliferating marrow when planning external beam radiation therapy [

64] or to evaluate

marrow reserve in haematological disorders.

18.5 Clinical Cases

thoracic region which on fused PET/CT and CT images (b–g) localised to enlarged bilateral mediastinal lymph nodes (subcarinal-~2.4×1.5cm, SUVmax 9.3)

FLT tracer is injected (200MBq for brain scans, 370 MBq for body scan), imaging can start immediately for a fully quantitative study over one area of the body, or after an uptake period of about 60–90min if whole-body semiquantitative imaging is being performed.

Low-dose CT (parameters: 80 mA, 140 kV,

0.8 s/tube rotation, and reconstructed slice thickness of 4.25mm) for attenuation correction is rst performed covering the vertex of skull to the second cervical vertebra/to the mid-thighs using a multi-detector helical CT scanner. PET is then acquired in the three-dimensional mode with a scan time of 7–30min. Data are reconstructed using the ordered subsets expectation maximisation (OSEM) algorithm with two iterations and 16 subsets, applying a matrix size of 128×128.

A 60-min dynamic protocol can be employed, immediately after injection or after incorporation time of 15–60min.

18.6

PET/CT andPET/MRI

Acquisition Protocols

18.6.1 PET/CT Protocol

The patient can be prepared by fasting for 4–6h, although this is not required, and rests for 15min before i.v. 18F-FLT administration. After the 18F-

18.6.2 PET/MRI Protocol

F-FLT is injected 60 min prior to PET/MRI acquisition. The exam is performed with supine positioning and head and body coils and additional prone breast PET/MRI with dedicated breast coils.

Body PET/MRI: A complete PET/MRI study includes whole-body coverage from the vertex to the mid-thigh. MRI data is acquired simultane-

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ously with PET data. A typical exam includes a T1-weighted DIXON sequences for attenuation, axial diffusion-weighted (DWI) echoplanar imaging (EPI), axial short tau inversion recovery (STIR) images, coronal and axial T2-weighted 2D and T1-weighted 3D images pre- and postgadolinium (Gd). Additional MRI diagnostic sequences can be selected based on specic body region (liver, pancreas, pelvis, breast, thorax, spine) or clinical indication (haematolymphoid malignancy) with dedicated tomographic planes, high resolution images, or whole-body diffusionweighted imaging with background body signal suppression (WB-DWIBS).

Brain PET/MRI: PET/MRI of the brain generally requires an attenuation correction with T1-weighted Dixon sequences, conventional multiplanar sequences with T1, T2, and DP-weighted images, diffuse imaging (DWI) using echoplanar sequences with calculation of the map of apparent diffuse coefcient (ADC), uid-attenuated inversion recovery (FLAIR) sequences, susceptibility weighted imaging (SWI), and T1 3D fat sat post-gadolinium images. Depending on clinical indication, advanced sequences such as perfusion weighted imaging (PWI), functional MRI, diffusion tensor imaging (DTI), and MR spectroscopy (MRS) can be selected.

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