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15 Radiolabeled FAPI
https://t.me/med1917
267
Fig. 15.3 Case of a 53-year-old female patient with
breast cancer, who underwent surgery and one cycle chemotherapy in combination of one cycle
177Lu-Trastuzumab. Comparison between 18F-FDG
PET/CT and 68Ga-FAPI PET/CT.Lymph node involvement in the left axilla (level I), right axilla (level II and
III), mediastinum (paratracheal, prevascular, subcarinal
and in the neck in levels II–V of the right side). Left sided
parietal lobe metastasis, detected only by 68Ga-FAPI
PET/CT. Multiple lung metastasis mainly in the right
lung. Sacral bone metastasis and pleural involvement in
the right lung was detected. Moreover,physiological high
uptake of FAPI was noted in the uterus. From Habibollah
Dadgar et al. Initial clinical experience using Ga-FAPI-46
PET/CT for detecting various cancer types. Hell J Nucl
Med. 2024;27(2):84–93 with permission
Fig. 15.4 Case of a patient with gastric adenocarcinoma
underwent gastrectomy and received CRT.Status: rising
tumor marker (CA 19–9) and recurrence evaluation.
Hypermetabolic cervical LN in the right side of the neck
(level 2) without FAPI uptake. FAPI uptake in the focal
peritoneal thickening in the midline of the abdomen at the
level of L2 (without hypermetabolism). From Habibollah
Dadgar et al. Initial clinical experience using Ga-FAPI-46
PET/CT for detecting various cancer types. Hell J Nucl
Med. 2024;27(2):84–93 with permission
268
https://t.me/med1917
A. Cimini et al.
15.6 PET/CT Acquisition Protocols
Considering the recent introduction of broblast
activation protein (FAP)-specic radiotracers in
clinical practice, well-established guidelines for
PET data acquisition have not yet been reported
for the different indications. Most of the studies
conducted on FAPI-PET imaging followed a
patient preparation procedure and acquisition
parameters/settings similar to 18F-FDG PET [84].
A signicant advantage of radiolabeled FAPIPET imaging with respect to patient preparation
is that this scan does not require any special
dietary preparation, fasting, and/or glycemic conditions since glucose metabolic pathways or
insulin-related metabolism is not involved as
opposed to 18F-FDG PET imaging where 6h fasting is commonly required. In this light, higher
patient compliance would be expected when a
FAPI-PET scan is prescribed, even for diabetic
patients with elevated serum glucose levels [17,
84]. However, in some studies, patients were
asked for minimum 2h of fasting prior to FAPIPET scan to minimize the impact of bile duct
excretion on the visualization/quantitative analysis of intrahepatic lesions [85].
Whole-body and total-body (from tip of skull
to mid-thigh) examinations are commonly
adopted in FAPI-PET scanning, wherein the
administered activity varies largely across the
different centers/protocols. The injected activity
in whole-body or total-body FAPI-PET examinations follows a general rule to meet a lower limit
of 100 MBq per scan to guarantee the clinical
value of the resulting PET images with respect to
the count rate statistics. According to dosimetry
studies, an upper limit of 370MBq was considered per scan as a radiation protection measure
(assuming an effective dose of 1.6mSv/100MBq)
[
10]. Most FAPI-PET examinations have been
conducted using an injected activity ranging from
1.8 to 3.7MBq/kg, while in comparative studies,
an injected activity ranging from 3.0 to 5.5MBq/
kg was considered in 18F-FDG PET [11, 84].
Overall, in comparative studies between 18F-FDG
and FAPI-based PET scans, half of 18F-FDG
radiopharmaceutical activity was considered in
FAPI scans [84].
The biodistribution and time-activity curve
analysis of FAPI-based radiotracers in dynamic
studies demonstrated that FAPI radiotracers’ stable biodistribution is achieved rapidly after radiotracer injection. Ten minutes to 3h post-injection,
normal tissue uptake did not exhibit considerable
changes in FAPI-based PET scans [
10, 22]. A
similar observation was made for malignant
lesions, wherein 10–18 min post-injection in
FAPI-PET scanning, the uptake in tumors
reached a high level and stayed at a similar level
up to 2h post-injection [64, 86, 87]. The possibil-
ity of early FAPI scanning would simplify the
clinical workow since mandatory 1-h uptake in
18
F- FDG PET scan could be avoided [10]. Most
FAPI-based PET studies in the literature were
conducted 30–60min post-injection.
FAPI-based PET examinations were performed on hybrid PET/CT scanners in most studies, whereas about 20% of the examinations were
conducted in PET/MRI scanners. Depending on
PET scanner models, an acquisition time of
2–5min per bed position was adopted in FAPIPET studies [17, 43]. For photon attenuation and
scatter correction, PET acquisitions on PET/CT
scanners were followed by either low-dose or
diagnostic contrast-enhanced quality CT imaging. Low-dose and diagnostic quality CT images
were acquired at tube currents of 30–50 mAs and
80–130 mAs, respectively, at a maximum beam
kilovoltage of 120–130 kVp [11, 64]. In hybrid
PET/MR scanners, due to the lack of transmission scanning to generate a patient-specic attenuation map, in-phase and out-of-phase MR
sequences are commonly acquired to generate
fat-and water-content images of the body. Then, a
four-class attenuation map containing predened
attenuation coefcients for background air, lung,
fat, and soft-tissue is generated for attenuation
and scatter correction [
88].
PET image reconstruction is performed using
conventional ordered subset expectation
maximization (OSEM) algorithm using different
iterations and subsets depending on the PET
scanner model (i.e., 2/21 iterations/subsets are
used on the Siemens Biograph mCT and 3/28
iterations/subsets on the GE SIGNA™ PET/
MRI). Time- of- ight information (if available) is
15 Radiolabeled FAPI
https://t.me/med1917
included within PET image reconstruction. The
PET emission data is corrected for randoms,
decay, photon attenuation, and scatter. Resolution
recovery or point spread function (PSF) modeling to compensate for spatial resolution degradation is considered within PET image
reconstruction. The average positron energy of
Ga-68 radionuclide used in FAPI-PET imaging is
0.83MeV, leading to an average positron range
of 3.5mm. In this regard, the spatial resolution of
68
Ga-FAPI PET images is inferior compared to
short-range radiotracers, such as 18F-FDG
(<1mm) [89]. PSF modeling specic to Ga-68
radionuclide could partly compensate for the spatial resolution degradation due to positron range.
In some GE Healthcare PET scanners, such as
the Discovery PET/CT scanner, Bayesian penalized likelihood image reconstruction algorithm
(Q.clear; GE Healthcare) is employed to reconstruct PET images. The penalization parameter β,
determining the levels of noise and signal recovery in the Q.clear algorithm, is commonly set to
500 or 750in FAPI imaging. Since the optimization of the β factor to achieve high-quality images
depends on PET acquisition, radiotracer uptake,
and indication, the β factor should be dedicatedly
optimized for FAPI-based PET imaging. To
reduce noise levels, FAPI-PET images undergo
post-reconstruction Gaussian lter with a kernel
within the range of 3–5mm.
For FAPI-PET scans performed at different
centers, the NEMA IEC body phantom (Data
Spectrum Corporation, Durham, NC, USA) is
commonly employed for SUV normalization.
This phantom contains six simulated lesion
spheres with different diameters, which are lled
with different activity levels to realize various
signal (tumor) to background ratios [
50].
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https://doi.
18
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F-FES
MariaRosariaRuggiero, RobertaVisentin,
andSalvatoreAnnunziata
16
Abbreviations
[18F]FDG [18F]-uorodeoxyglucose
[18F]FES 16α-[18F]uoroestradiol
BC Breast cancer
E2 Estradiol
ER Estrogen receptors
FDA Food and Drug Administration
GPER G protein-coupled estradiol receptor
PET/CT Position emission tomography/com-
puted tomography
SHBG Sex hormone binding globulin
SUV Standardized uptake value
M. R. Ruggiero (*) · R. Visentin
Nuclear Medicine Unit, Department of Radiology
and Oncologic Radiotherapy, Fondazione Policlinico
Universitario A. Gemelli IRCCS, Rome, Italy
Medipass S.P.a. Servizio Integrativo PET TC,
Radiofarmacia Fondazione Policlinico Agostino
Gemelli IRCCS, Rome, Italy
mariarosaria.ruggiero@guest.
e-mail:
policlinicogemelli.it; roberta.visentin@medipass.it
S. Annunziata
Nuclear Medicine Unit, Department of Radiology
and Oncologic Radiotherapy, Fondazione Policlinico
Universitario A. Gemelli IRCCS, Rome, Italy
e-mail:
Salvatore.annunziata@policlinicogemelli.it
16.1 Synthesis
16α-[18F]uoroestradiol ([18F]-FES), the radiouorinated homolog of estradiol (Fig.16.1), has
been the rst positron emission tomography
(PET) imaging agent for a receptor target in cancer. [18F]-FES was born in late 1974, thanks to the
collaboration of Katzenellenbogen and Welch
when they decided to switch isotope to uorine 18 after the challenges encountered in the initial
attempt of imaging breast tumors with bromine 77 labeled estrogen [1]. [18F]-FES was rst produced in 1984 by a two-step method comprising
the 18F-nucleophilic substitution of a bistriate
precursor (Fig. 16.2) [2, 3]. Since then various
attempts have been made in order to optimize
[18F]-FES production parameters (yield, quality,
and molar activity) [4–16], moving from manual
to fully automated procedure, using one-pot production routes based on diverse precursors, the
most convenient a cyclic sulfate precursor
(Fig.
16.2) and different purication methods.
Although nowadays available on the market,
approved for clinical use in France in 2016 and in
the USA in 2020 with the trade name EstroTep
[17] and Cerianna [18], respectively, [18F]-FES
still attracts the interest of radiochemists looking
for further improvements [19–21].
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
F. Calabria, O. Schillaci (eds.), Radiopharmaceuticals,
https://doi.org/10.1007/978-3-031-54196-4_16
273
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M. R. Ruggiero et al.
Fig. 16.1 Chemical
structure of 16α-[
uoroestradiol
18
([
F]-FES) and estradiol
18
F]-
Fig. 16.2 Summary of the main radiosynthesis approaches
16.2 Pharmacokinetics
[18F]-FES acts as the analogous estradiol, the
most active form of estrogen that produces many
physiological effects primarily by regulating
gene expression through the specic estrogen
receptors (ERs) binding [22] (Fig.16.3 created
with BioRender.com). ER is highly expressed in
70–80% of breast cancers and plays a central role
in prognosis and treatment selection for patients
with breast cancer [23–25]. Approximately, 45%
of circulating [18F]-FES is bound to the transport
protein sex hormone binding globulin, SHBG,
and the remainder is weakly bound to the more
abundant albumin [26, 27]. The interaction of
SHBG/ [18F]-FES/ERs is debated suggesting
both scenarios of facilitated uptake and hindered
uptake [28–30]. [18F]-FES as a lipophilic, steroidbased compound is rapidly extracted from the
plasma and metabolized by the liver [31]. After
the excretion of labeled glucuronide and conjugation metabolites into the bile, they are efciently resorbed via the enterohepatic circulation
system with minimal radiotracer reaching the
large intestine [26]. Once released back into the
plasma, the reabsorbed metabolites are excreted
into the urine by the kidneys (Fig.16.4 created
with BioRender.com). Since the rates of hepatic
16 18F-FES
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275
Fig. 16.3 Schematic representation of estradiol (E2)
pathways: Estrogen receptors (ER), alfa (ERa), and beta
(ERb); transport protein sex hormone binding globulin,
Fig. 16.4 Enterohepatic cycle to describe the pathway
involved in the metabolism of [
18
F]-FES
release\renal excretion are similar, the result is a
relatively stable metabolite background activity
with labeled metabolites excreted and not trapped
in tissue [31, 32]. Approximately 20min after
administration, about 20% of the total circulating
SHBG and paired receptor; G protein-coupled estradiol
receptor, GPER. [
expression
18
F]-FES binds ER to detect ER
activity is in the form of the non-metabolized
radiotracer, while the remaining is as radiolabeled metabolites [31].
16.3 Pharmacological
Distribution
The recommended administered activity is
222MBq (6mCi), with an acceptable range of
111–222MBq (3–6mCi) [18]. The normal biodistribution of [18F]-FES involves the main
organs of the metabolism and excretion (liver,
biliary system, bowel, kidneys, ureters, bladder)
as well as highly ER-expressing organs (uterus),
shown in Fig.16.5 [18, 26, 33]. The organ doses
are comparable to those routinely used in
nuclear medicine tests and the associated potential radiation risks are within acceptable limits
[26, 33].The optimal diagnostic imaging is performed at 60–80min post-radiotracer injection
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M. R. Ruggiero et al.
a
b
Fig. 16.5 Normal biodistribution of [18F]-FES. (a)
Coronal [
demonstrating normal [
bowel, portal vein (white arrow), and bladder. (b) Coronal
18
F]-FES PET, CT, and fused [18F]-FES PET/CT
considering its own rapid clearance from the
blood pool and stable background activity.
Earlier imaging could potentially be performed
as early as 20 min post- injection [18, 26] to
decrease the background bowel activity due to
the presence of [18F]-FES labeled bile. This
approach could be particularly useful to prevent
false negatives in patients with metastatic lobu-
18
F]-FES uptake in the liver, small
18
[
F]-FES PET, CT, and fused [18F]-FES PET/CT demonstrating normal [
vises, bladder, and uterus (black arrow). (Adopted by
O’Brien etal. [26])
18
F]-FES uptake in the liver, renal pel-
lar carcinoma, known to metastasize to the gastrointestinal tract [34]. Thanks to more sensitive
PET scanners, delayed imaging in the 2–6 h
range might help in the visualization of liver
lesions. Although the absorption of [18F]-FES
appears to be stable over time in most breast
cancers, hepatic activity related to its metabolism resolves over time [31].
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