Radiopharmaceuticals A Guide to PET/CT and PET/MRI 2nd

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To Nicoletta, Maria Beatrice and Agnese Felicia.
O.S.
To my father, my principal sponsor.
F.C.
Preface

Two years have elapsed since the publication of the book Radiopharma­
ceuticals, a well-received volume reflecting the state of the art in hybrid
PET/CT and PET/MR imaging with novel radiopharmaceuticals. Since its
publication, the necessity to cover a larger spectrum of PET tracers has
emerged, allowing physicians, residents, and students to deepen their knowl-
edge about PET molecular imaging in a single volume.
Therefore, this edition is enriched by two new chapters, respectively, that
focus on prostate cancer imaging with 68Ga-PSMA and imaging of tau pathol-
ogy. Previous chapters are also updated by new interesting clinical cases and
novel applications.
The panorama of PET molecular imaging has been improved in the last
decades by the development of several novel radiopharmaceuticals; some of
them play an established role while other tracers are showing interesting pre-
liminary results.
In this scenario, the most useful PET tracer, the 18F-FDG, shows a limited
role in several diseases due to its intrinsic molecular properties while PET
imaging is increasingly changing into a diagnostic technique, where the
radiopharmaceuticals rather than the scanner can help clinicians in reaching
the diagnostic goal. Therefore, amino acid tracers, radiolabeled choline, amy-
loid tracer, and other radiopharmaceuticals are becoming a valid alternative
to 18F-FDG in specific clinical settings.
Nevertheless, all PET tracers do not completely satisfy an important char-
acteristic of the “ideal tracer”: the capability to be largely, quickly, and selec-
tively taken up at the target site.
Moreover, the PET imaging has been rapidly improved by the develop-
ment and commercial availability of hybrid PET/CT and, more lately, PET/
MRI scanners, which afford us to enlarge our understanding on the applica-
tions of molecular imaging, taking advantage of the concurrent functional
and anatomical depiction of the human body.
For the reasons above expressed, the aim of our work is to describe the
most common tracers actually used in PET imaging. An essential, synthetic
chapter is still targeted on the 18F-FDG, the “milestone” among radiopharma-
ceuticals, in order to describe its actual applications, with a specific para-
graph focused on 18F-FDG PET/MRI.

vii
viii Preface

Thereafter, several novel tracers are presented in each chapter. For all of
them, we have described bio-distribution, physiopathology, and kinetics,
aiming to describe their specific “molecular pathways.” For all tracers, we
have tried to provide the essential diagnostic features and the most common
clinical indications. Moreover, a special paragraph in each chapter describes
and comments some diagnostic pitfalls which can occur in clinical practice,
while another paragraph describes the most used PET/CT acquisition
protocols.
A special interest is given to a large number of clinical cases (more than
170 figures in this new edition), in order to get the reader close to the typical
imaging features, pathologic findings, or to the diagnostic pitfalls of all
radiopharmaceuticals.
Figures of our book (with several multimodal imaging pictures) also try to
achieve different goals, as follows:

• Compare potential differences between SPECT and PET imaging

• Show the importance of the hybrid-integrated evaluation of PET/CT imag-
ing with the expertise on CT diagnostic criteria
• Describe the added value of contrast-enhanced PET/CT in some limited
cases
• Explain mismatches or overlapping among two different radiopharmaceu-
ticals in the same patient
• Realize all the potentiality of correlative MRI and of the hybrid PET/MRI
evaluation

Considering the continuous innovation process of nuclear medicine, all

chapters are focused on the role of a single tracer or few radiopharmaceuti-
cals. Actually, some chapters are focused on the amino acid radiopharmaceu-
ticals, such as 11C-methionine, 18F-DOPA, and 18F-FET. All these tracers are
useful for brain tumor imaging with some analogies, but we have also tried to
describe some peculiar applications beyond neuro-oncology.
A specific chapter is focused on “radiolabeled choline,” including all vari-
ants of this useful tracer: 11C-choline, 18F-methylcholine, and 18F-ethylcholine.
This chapter is also enriched by new interesting cases, bibliography, and
applications other than prostate cancer.
Other important chapters concern imaging of the skeletal system by 18F-­
NaF, the myocardial perfusion imaging with 82Rb, and the β-amyloid imaging
of dementia.
Considering the importance of targeted radionuclide therapy, two chap-
ters, respectively, regard PET/CT imaging with 68Ga-labeled somatostatin
receptors analogs and the therapy with 223Ra.
A special section is also focused on the 64Cu as a versatile nuclide for PET
imaging, its possible ligands PSMA, ATSM, and DOTATOC, and their poten­
tial clinical applications.
Preface ix

As in the previous edition, particular mention is given to fields other than

oncology. In fact, new approaches are described in the study of brain tumors,
urological malignancies, functional imaging, forensic use, and the evaluation
of phlogosis and inflammation.
Humbly, we still hope to have centered our ambitious and arduous scope,
without exceeding technical aspects, trying to give the readers (clinicians,
nuclear medicine physicians, radiologists, and young colleagues or students)
an easy-to-consult, practical and concise atlas guide to the PET, PET/CT, and
PET/MR molecular imaging with novel radiopharmaceuticals.

Cosenza, Italy Ferdinando Calabria

Rome, Italy  Orazio Schillaci
Contents

1 18F-FDG��������������������������������������������������������������������������������������������   1
Ferdinando Calabria, Andrea Cimini, Antonio Bagnato,
Domenico Gullà, Giuseppe L. Cascini, Nicoletta Urbano,
and Orazio Schillaci
2 
18
F-DOPA������������������������������������������������������������������������������������������ 37
Ferdinando Calabria and Orazio Schillaci
3 Lipogenesis Pathway: Radiolabeled Choline�������������������������������� 57
Ferdinando Calabria, Marzia Colandrea, Giuseppe L. Cascini,
and Orazio Schillaci
4 18F-FET���������������������������������������������������������������������������������������������� 83
Giorgio Treglia, Barbara Muoio, and Luca Giovanella
5 18F-NaF���������������������������������������������������������������������������������������������� 89
Ferdinando Calabria and Orazio Schillaci
6 Somatostatin Receptor Analogs (68Ga-DOTATOC,
68
Ga-DOTANOC, 68Ga-DOTATATE)���������������������������������������������� 99
Luca Filippi, Patrizia Pizzichini, Oreste Bagni,
and Francesco Scopinaro
7 64Cu-Radiopharmaceuticals������������������������������������������������������������ 115
Ferdinando Calabria, Antonio Bagnato, Vincenzo Gangemi,
Rosina Paonessa, Mario Leporace, Nicoletta Urbano,
and Giuseppe Lucio Cascini
8 Amyloid Imaging������������������������������������������������������������������������������ 131
Agostino Chiaravalloti, Ferdinando Calabria,
Antonio Bagnato, and Orazio Schillaci
9 PET Myocardial Perfusion Imaging: 82Rb������������������������������������ 143
Maria Luisa De Rimini and Giovanni Borrelli
10 The Bone Pathway: 223Ra-Dichloride �������������������������������������������� 179
Laura Evangelista and Alessandra Zorz
11 11C-Methionine �������������������������������������������������������������������������������� 193
Sebastiano Cosentino, Fabrizio Scopelliti, Gabriella Murè,
Sara Baldari, and Massimo Ippolito

xi
xii Contents

12 68Ga-PSMA �������������������������������������������������������������������������������������� 211

Robert Pichler, Johannes Wolfsgruber, Ferdinando Calabria,
Orazio Schillaci, and Andreas Dunzinger
13 PET Biomarkers for Tau Pathology ���������������������������������������������� 227
Antoine Leuzy, Kerstin Heurling, and Michael Schöll
 18
F-FDG
1
Ferdinando Calabria, Andrea Cimini,
Antonio Bagnato, Domenico Gullà,
Giuseppe L. Cascini, Nicoletta Urbano,
and Orazio Schillaci

Contents
1.1     Synthesis 2
1.2     Pharmacokinetics 2
1.3     Physiological Distribution 3
1.4     Clinical Indications 5
1.4.1  Differentiation Between Benign and Malignant Lesions 5
1.4.2  Unknown Primary Tumor 5
1.4.3  Staging 6
1.4.4  Restaging 9
1.4.5  Assessment of Response to Therapy 9
1.4.6  Detection of Tumor Recurrence 11
1.4.7  Radiation Therapy Planning 14
1.4.8  Inflammation and Infection 15
1.4.9  Neuroimaging 16
1.4.10 Myocardial Viability 21
1.5     PET/CT Acquisition Protocols 21

Authors declare they have obtained permission for any

previously published material used in their chapter.

F. Calabria (*) · A. Bagnato

G. L. Cascini
Department of Nuclear Medicine and Theranostics,
Nuclear Medicine Unit, Department of Diagnostic
“Mariano Santo” Hospital, Cosenza, Italy
Imaging, Magna Graecia University, Catanzaro, Italy
e-mail: [email protected]
N. Urbano
A. Cimini
Nuclear Medicine Unit, University Hospital
Department of Diagnostic Imaging, Molecular
“Tor Vergata”, Rome, Italy
Imaging, Interventional Radiology and Radiotherapy,
University Hospital Tor Vergata, Rome, Italy O. Schillaci
Department of Biomedicine and Prevention,
D. Gullà
University “Tor Vergata”, Rome, Italy
Neuroimaging PET/MRI Research Unit, Institute of
Molecular Bioimaging and Physiology, Italian National Department of Nuclear Medicine and Molecular
Research Council, IBFM-CNR, Catanzaro, Italy Imaging, IRCCS Neuromed, Pozzilli, IS, Italy

© Springer Nature Switzerland AG 2020 1

F. Calabria, O. Schillaci (eds.), Radiopharmaceuticals,
https://doi.org/10.1007/978-3-030-27779-6_1
2 F. Calabria et al.

1.6     PET/MRI 21
1.7     Variants and Pitfalls 29
References 34

Abbreviations
bacterial endotoxin. These tests should be fin-
F-FDG
18 18
F-Fluoro-deoxyglucose ished after the tracer can be released [2].
BOLD Blood oxygenation level
dependent
FLAIR Fluid attenuation inversion 1.2 Pharmacokinetics
recovery
MIP Maximum intensity projection Being an analog of glucose, the 18F-FDG plays
MRI Magnetic resonance imaging an undisputed role in PET imaging, due to its
PET/CT Positron emission tomography/ versatility as marker of cellular metabolism.
computed tomography
18
F-FDG enters the cell by the same membrane
ROI Region of interest transport mechanism as glucose. After penetra-
SPECT/CT Single photon emission computed tion of the cellular membrane via glucose trans-
tomography/computed tomography porters [3], both 18F-FDG and glucose are
SUVmax Maximum standardized uptake phosphorylated by hexokinase. Unlike glucose-
value 6-phosphate, 18F-FDG-6-phosphate is not a
substrate of glucose-­ 6-phosphate isomerase
and does not undergo further metabolism in the
glucose pathway. Therefore, 18F-FDG remains
trapped within cells (Fig. 1.1). The increased
1.1 Synthesis glucose utilization in tumor cells is due to three
main reasons: overexpression of membrane
18
F-FDG is a glucose analog with the hydroxyl glucose transporters, increased hexokinase
group on the 2-carbon of a glucose molecule activity, and decreased levels of glucose-
replaced by 18F, a β+ emitter isotope of Fluorine. 6-phosphatase [4].
18
F-FDG can be synthesized by either electro- Physiologically, the tracer is taken up in cells
philic or nucleophilic fluorination reactions. with high metabolism or gradient of glucose
The first synthesis of 18F-FDG was obtained in uptake, as in the brain. First studies on
1976 by electrophilic fluorination [1]. Instead, 14
C-deoxgyglucose as imaging agent well dis-
the chemical reaction of nucleophilic substitu- played that synapses metabolism is strictly related
tion involves the addition of a nucleophilic mol- with neuronal cells metabolism [5].
ecule (a negatively charged molecule) into a Subsequently, the 18F-FDG has been success-
molecule with a leaving group (electron draw- fully employed as tumor imaging marker, since it
ing group attached to the parent molecule provides useful functional information based on
through an unstable chemical bond). the increased glucose uptake and glycolysis of
Nucleophilic fluorination, using mannose tri- cancer cells. Moreover, after the antiblastic ther-
flate as precursor and tetrabutylammonium apy, this tracer can be considered as marker of
salts, is largely used because of the high yield response to therapy, owing to show the decrease
and short reaction time [2]. The main quality of glucose metabolism in cancer cells, after
control requirements of 18F-FDG regard the therapy.
identity of radionuclide, radiochemical purity, The clearance of 18F-FDG is rapid and involves
pH, residual solvent, sterility, and the level of the renal system, through a filtration process of
1 18
F-FDG 3

Fig. 1.1 Being an analog of glucose, the 18F-FDG is internalized in cells and phosphorylated

18
F-FDG from blood pool into kidneys and a reticuloendothelial cells, spleen and bone marrow
rapid production of radioactive urine, are usually characterized by mild uptake. The liver
starting few minutes after the intravenous usually shows high gradient of uptake while kid-
administration. neys, ureters, and bladder are normally visualized
at PET imaging, due to the tracer renal excretion
(Fig. 1.2). A certain grade of vascular activity can
1.3 Physiological Distribution also be observed, especially for early imaging, in
mediastinal vascular structures or in the iliac arter-
The physiological distribution of 18F-FDG con- ies. Finally, other sites of mild uptake are salivary
cerns organs or tissues with high rate of glucose and lachrymal glands, pancreas, stomach, and, due
metabolism: in the brain, this radiopharmaceuti- to the peristaltic activity, the intestinal loops, with
cal is normally taken up in the normal structures large intra-individual variability.
of gray matter, basal ganglia, cerebellum, and Among some physiopathological features of
thalamus. A lower uptake gradient can be bio-distribution of the 18F-FDG should be primar-
observed in the glial cells of the white matter, ily considered the possibility of a diffuse homoge-
rectus muscle of the eye, medial and lateral, can neous bone marrow uptake, which usually reflects
show tracer uptake due to physiologic activity. hyperplastic bone marrow which can be docu-
The myocardium normally can show high mented in patients undergoing chemotherapy
­ F-­FDG uptake, with a certain variability, since
18
(Fig. 1.3).
glucose is not the primary metabolic substrate of Several methods are available for measuring
the myocardium. Due to the high affinity of the the rate of 18F-FDG accumulation in tissues. PET
4 F. Calabria et al.

Fig. 1.2 Physiological

whole body 18F-FDG
a b
bio-distribution in a
42-year-old male subject
(a) and a 36-year-old
female subject (b)

a a´ b c

b´ c´

Fig. 1.3 18F-FDG 3D PET maximum intensity projection chemotherapy. As evident in axial PET/CT (b, c) and CT
in coronal (a) and lateral (a’) views shows diffuse physi- (b’, c’) details, no morphological abnormalities are asso-
ological uptake in the skeleton of a 45-year-old woman, ciated with functional findings
due to bone marrow activation, 15 days after the end of
1 18
F-FDG 5

scanners are designed to measure the in vivo or in assessing the metabolism of uncertain find-
radioactivity concentration [kBq/mL], which is ings at conventional radiologic imaging. 18F-FDG
directly linked to the tracer concentration. PET/CT can be useful for the characterization of
However, it is the relative tissue uptake of 18F-­ enlarged lymph nodes, in the differential diagno-
FDG that is of interest. The two most significant sis among benign and malignant lesions of the
sources of variation that occur in practice are the bones and soft tissues. One of the most important
amount of injected 18F-FDG and the patient size. field of applications of 18F-FDG PET is the evalu-
To compensate for these variations, the standard- ation of solitary lung node: to date, the 18F-FDG
ized uptake value (SUV) is used as a relative PET/CT allows to simultaneously evaluate the
measure of 18F-FDG uptake as it represent the metabolism of the lung nodes and to depict, by
most commonly used semiquantitative parameter the measurement of the SUVmax, which can
for analysis of oncology PET studies. improve the visual assessment of PET data in a
The SUV is a semiquantitative value express- clinical context [11]. In particular, it has been
ing degree of metabolic activity in selected tis- showed that a SUVmax > 2.5 is frequently asso-
sues [6], by using a region of interest (ROI), and ciated with a possibility of malignant nature of
can be obtained by the following formula: lung nodules. However, correlative CT imaging
can also improve the specificity of PET imaging,
SUV  r  a  / w  allowing the concurrent possibility to describe
morphologic findings as size, margins, eccentric
where r is the radioactivity activity concentration calcifications or to ensure the contrast enhance-
[kBq/mL] measured by the PET scanner within a ment, when administered [9]. Anyway, the meta-
ROI, a′ is the decay-corrected amount of injected bolic depiction of the pulmonary lesion is a
radiolabeled FDG [kBq], and w is patient weight significant information, especially for those lung
[7]. Moreover, the maximum standardized uptake nodes without evident radiographic characteris-
value (SUVmax) is the maximum number of tics of malignancy (Fig. 1.4). On the other hand,
counts within the pixels in a ROI and can be con- nuclear medicine physicians cannot exclude the
sidered the actual semiquantitative measure use- possibility of malignancy in some histological
ful in assessing 18F-FDG rate of uptake in tissues. types of lung cancer, without significant glucose
A SUVmax cutoff value of 2.5 is commonly metabolism, as for bronco-alveolar carcinoma
used to differentiate between benign and malig- [12]: the accurate knowledge of the CT diagnos-
nant lesions in PET/CT [8]; however, there are a tic criteria is of the utmost importance, allowing
significant number of false positives (due to to consider the PET/CT as an unique, hybrid,
inflammatory diseases) and false negatives (due single session, whole body imaging modality
to low-grade malignancies) [9]. It is necessary to with an useful overall diagnostic accuracy.
state that, in oncology 18F-FDG PET is generally
assessed using visual criteria, looking for a focal
area of increased uptake that can be compatible 1.4.2 Unknown Primary Tumor
with malignancy, in the clinical context [10].
Unknown primary tumors are a heterogeneous
group of metastatic malignancies in which the
1.4 Clinical Indications primary tumor could not be detected despite
diagnostic evaluation. Generally, these tumors
1.4.1 Differentiation Between are characterized by the presence of a metastatic
Benign and Malignant Lesions lymph nodal disease, evident at conventional
imaging (CT and/or MRI), with positive histo-
For its peculiar molecular properties, the 18
­ F-­FDG logical exam for malignant cells and no evidence
is successfully employed in the differential of the primitive lesion [10]. The unknown
diagnosis between malignant and benign lesions, primary tumors are aggressive diseases, with a
6 F. Calabria et al.

a b

Fig. 1.4 Metabolic evaluation of a node in the right lung. uptake in the lesion. Axial CT (c) and PET/CT (d) views
PET 3D maximum intensity projection (a) and corre- display a 1-cm wide node with regular margins and with-
sponding axial PET view (b) do not show significant out characteristics of malignancy

poor survival, ranging from only 2 to 10 months ensure the diagnosis with CT and to the very poor
from the diagnosis. Anyway, it can be hypothe- diagnostic accuracy of conventional imaging on
sized that the detection of the ­primary tumor may this topic.
optimize treatment planning and, therefore,
patient prognosis [13]. Despite a low diagnostic
performance of 18F-FDG PET/CT in detecting 1.4.3 Staging
unknown primary tumors (Fig. 1.5), ranging
from 25% to 43% in several meta-­analysis [14], One of the main indications for 18F-FDG PET/CT
this diagnostic tool should be considered as first- is the staging of patients with known malignan-
line imaging method, due to the challenge to cies, due to the capability in assessing tumor
1 18
F-FDG 7

a b

Fig. 1.5 Patient with multiple metastases of unknown Axial PET (b), CT (c), and PET/CT (d) views show focal
primary tumor. 18F-FDG 3D PET Maximum intensity pro- and intense uptake in the tail of the pancreas (final histo-
jection (a) shows multiple areas of pathologic tracer logical diagnosis: pancreas carcinoma)
uptake in the brain, lungs, skeleton, thorax, and abdomen.

extension, lymph node metastases, and bone sec- l­imited to, the following: lung cancer [16],
ondary lesions [15]. In fact, the hybrid PET/CT locally advanced breast cancer (Fig. 1.6) [17],
evaluation, with and without contrast media sarcoma [18], lymphomas (Fig. 1.7) [19], colon
administration, also provides in a single whole cancer [20], gynecological malignancies [21],
body scan to rapidly obtain information ­regarding and other kinds of tumor with high grade of glu-
the primitive tumor and metastases, in order to cose metabolism which potentially can be radi-
choice the best therapeutic approach. cally treated. 18F-FDG PET-CT can also be used
Indications for 18F-FDG PET/CT during the as a problem-­solving tool to establish the base-
staging of solid tumors include, but are not line staging before commencing treatment in
8 F. Calabria et al.

a b e

c f

d g

Fig. 1.6 A 56-year-old woman examined for staging evident in corresponding axial PET views (b, e). The
locally advanced breast cancer. PET 3D maximum inten- uptake was linked to a 3.2-cm-wide node in the breast and
sity projection (a) shows pathologic uptake in the upper to a 1-cm-wide metastatic lymph node, as showed in cor-
outer quadrant of the right breast (red arrow) and a further responding CT (c, f) and PET/CT views (d, g)
area of uptake in the ipsilateral axilla (black arrow), as

a b c

d e

Fig. 1.7 In a patient with splenic lymphoma, PET 3D evident in PET/CT (b, c) and contrast-enhanced CT (d, e)
maximum intensity projection (a) shows abnormal tracer coronal and axial views
uptake in the spleen, in association with splenomegaly, as
1 18
F-FDG 9

a c

b d

Fig. 1.8 In a patient with dorsal melanoma, axial PET/ occipital regions of the left cerebral hemisphere, due to
CT and CT views (a, b, and c) show three foci of abnor- hyperdense lesions (arrows), also evident in PET 3D max-
mal 18F-FDG uptake in subcortical frontal, parietal, and imum intensity projection of the brain (d)

gastro-intestinal stromal tumors [22] and in head malignancies [27] and ovarian (Fig. 1.9) and
and neck cancer and prior to radical nodal resec- esophageal cancer [28]. Also in this clinical set-
tion in patients with suspicion of metastatic mel- ting, 18F-FDG PET/CT has proven to be more
anoma (Fig. 1.8) [23]. accurate modality than CT for assessment of
18
F-FDG PET/CT is also a valid guide to recurrence [29].
biopsy of suspected secondary bone lesions from
somatic tumors [24] or in detecting the best site
to perform biopsy. In fact, 18F-FDG PET/CT has 1.4.5 Assessment of Response
the advantage to accurately differentiate viable to Therapy
from nonviable tissues. This feature can reduce
inconclusive biopsy results by specifically target- Being an in vivo marker of tumor growth and
ing areas of viability showing high rate of glu- vitality, the 18F-FDG is useful for characteriza-
cose metabolism [25]. tion of cancer cells metabolism during the time,
especially for evaluating the response to therapy
(chemotherapy and/or radiotherapy). In oncol-
1.4.4 Restaging ogy, this approach can be directly applied in eval-
uating disease progression or in detecting the
18
F-FDG PET/CT is also useful in detecting reduction of tumor metabolism [30], allowing to
tumor recurrence in patients with solid tumors exceed limits of conventional anatomical imag-
previously treated for curative intent. The diag- ing (Fig. 1.10).
nostic performance of the exam is accurate espe- On this topic, the “interim PET” with ­18F-­FDG,
cially in patients with rising tumor markers [26], and its comparison with the “baseline PET,” has
suggestive for tumor relapse. Other tumors which become a milestone for the imaging of ­lymphomas.
can be evaluated during this phase are urological In particular, in patients with Hodgkin lymphoma,
10 F. Calabria et al.

a b e

c f

d g

Fig. 1.9 Restaging in a 55-year-old patient with ovarian uptake in the pelvis (red arrow) with multiple metastases
cancer and rising level of Ca-125, previously submitted to in lungs (b, c, d) and liver (e, f, g), as evident in axial PET,
surgical intervention of isteroannessiectomy. PET 3D CT, and PET/CT details
maximum intensity projection (a) shows pathologic

a b d

c e

Fig. 1.10 A patient examined 3 months after radiother- post-actinic necrosis, as evident in axial 18F-FDG PET (b)
apy for lung cancer. PET 3D maximum intensity projec- and PET/CT (c) views. Relative CT views (d, e) confirm a
tion (a) shows pathologic tracer uptake in the upper lobe lung lesion with irregular borders and pleural infiltration
of left lung, with internal core of hypometabolism due to