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R. Pichler et al.
Fig. 12.9 This patient presented multifocal osseous and lymph node metastases with high uptake of 68Ga-PSMA.A
therapeutic option with 177Lu-PSMA was suggested
12 68Ga-PSMA
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227
Fig. 12.10 Massive osseous metastasis is presented here by 68Ga-PSMA, some positive lymph node metastases were
observed as well
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R. Pichler et al.
Fig. 12.11
clearly a local relapse and bone metastasis in the pelvis, a
small lymph node right to the aortal bifurcation is hardly
SPECT/CT images of Tc99m-PSMA show
visible on the fusion images. This method is an alternative
when a PET scanner or a gallium generator is not
available
12 68Ga-PSMA
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Fig. 12.11 (continued)
229
12.5 PET Radioligands
forProstate Cancer Imaging
PET with choline tracers—labeled with 11C or
18
F—has historically found widespread use for
the diagnosis of (metastatic) prostate cancer.
However, choline metabolism is not increased in
a substantial number of cases. When compared
head-to-head, 68Ga-PSMA PET/CT outperforms
standard 18F-choline PET/CT, especially at low
PSA levels [25].
Considering 68Ga labeled PSMA, a variety
of agents is available with presumable very
similar clinical value. 68Ga-HBED-CC-PSMA
or 68Ga-PSMA-11 [26], and 68Ga-DOTATAGAFFK, termed PSMA I&T [22] are frequently
used. Variants labeled with 64Cu are available,
especially considered if the supply with 68Ga is
logistically demanding. 18F labeled PSMA PET
tracers have already been evaluated, as
18
F-DCFBC [26], and have already reached the
market in Europe. Newer 18F labeled agents are
18
F-DCFPyL and 18F-PSMA-1007 [14]. A possible advantage is less renal excretion which
facilitates the evaluation of the prostate bed.
A different approach related to amino acid
metabolism—the tracer mirrors the upregulation of transmembrane amino acid transport
[27]—is applied by the use of 18F-uciclovine
(18F-FACBC) to image prostate cancer tissue.
One advantage is that kidney uptake of uciclovine is negligible and no relevant activity in
the urinary tract can be observed, see
Fig.
12.12. As the method is relatively new,
Fig. 12.12 18F-Fluciclovine PET/CT had been helpful to identify a local relapse of prostate cancer—due to the fact that
there is no relevant uptake of this tracer in urine
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R. Pichler et al.
clinical usefulness and superiority to cholinePET have already been demonstrated [11,
28, 29], but equal clinical value compared
head-to-head to 68Ga-PSMA could not to be
shown.
12.6 PET/CT Acquisition Protocols
In general, PET/CT images are obtained about
60min after i.v. bolus application of an activity
of 200–250MBq 68Ga-PSMA [30] or 1.8–2.2 per
kilogram bodyweight [31]. Sufcient hydration
is recommended, the administration of diuretics—e.g. furosemide 20mg—is frequently used
[31]. It has been shown that imaging 3h after
injection can reveal more lesions characteristic
for prostate cancer with a higher uptake and contrast [32]. Anyhow, practical considerations as
patient management and the half-life of the tracer
have to be kept in mind.
A diagnostic or low-dose CT scan is generally
performed from base of the skull-base to midthigh [31], followed by acquisition of PET
images according to the specic scanner and the
manufacturer’s instructions. In our institution in
Linz, we frequently perform additional late
regional images, e.g. of the pelvis approximately
1h later when indicated after evaluation of the
PET/CT images already acquired before. When
using an 18F-PSMA tracer this approach is less
frequently necessary, see Fig.12.13.
Fig. 12.13 18F-PSMA PET of a patient with multiple
osseous and liver metastases—those capture the tracer but
to a lesser extent than the surrounding liver parenchyma.
Histology proofed poorly differentiated metastasis of an
adenocarcinoma of prostate origin
12 68Ga-PSMA
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231
12.7 Variants andPitfalls
Comparable to the experience with 18F-FDG and
18
F-FET, the usage of 68Ga-PSMA revealed a
growing body of evidence for pathological or
marked uptake in diverse anatomical structures, in
this case unrelated to prostate cancer. As a major
goal of PSMA imaging is the detection of lymph
node metastases, unspecic uptake in coeliac ganglia was among the rst reported pitfalls [33]. The
uptake of active granulomatous lesions in sarcoidosis, especially in the lung, can appear quite
impressive [4]. Paget’s disease has also been suggested as a potential clinical mimicker of bone
a
metastasis on PSMA-targeted PET imaging [4]. In
general terms, augmented bone metabolism might
be detected by moderate tracer uptake, as in postfracture healing. A variety of benign etiologies for
focal intense PSMA PET uptake have been published mostly in the form of case reports [34, 35].
A potential for specic oncologic imaging of
different malignancies has also been presented,
as for renal cell carcinoma [8] and hepatocellular
carcinoma [36]. Of special interest is the marked
uptake in endothelium in angiogenesis, which
has been proven by immunohistochemical staining. Thereby the imaging of primary brain gliomas—see Fig.12.14—and brain metastases can
b
c
Fig. 12.14 Images of multilocular glioblastoma, the
lesion is presented via MRI (a).
neovascularization of the glioma, mostly surrounding the
68
Ga-PSMA shows the
d
tumor (b, c), the shape appears different to the metabolic
imaging via
18
F-FET (d)
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be enabled [37–39]. Monitoring of bevacizumab
therapy might be possible by this imaging
method.
Clinical Cases
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PET Biomarkers forTau Pathology
https://t.me/med1917
AntoineLeuzy, KerstinHeurling,
andMichaelSchöll
13
13.1 Tau PET Tracers
The protein tau was rst described in 1975 as a
neuronal factor associated with the assembly and
stability of microtubules [1]. Though additional
functions have since been recognized for tau [2],
its role in maintaining the microtubule-based
cytoskeleton via binding to tubulin is regarded as
A. Leuzy
Clinical Memory Research Unit, Department of
Clinical Sciences, Lund University, Malmö, Sweden
Wallenberg Centre for Molecular and Translational
Medicine and The Department for Psychiatry and
Neurochemistry, The Sahlgrenska Academy,
University of Gothenburg, Gothenburg, Sweden
K. Heurling
Wallenberg Centre for Molecular and Translational
Medicine and The Department for Psychiatry and
Neurochemistry, The Sahlgrenska Academy,
University of Gothenburg, Gothenburg, Sweden
M. Schöll (*)
Clinical Memory Research Unit, Department of
Clinical Sciences, Lund University, Malmö, Sweden
Wallenberg Centre for Molecular and Translational
Medicine and The Department for Psychiatry and
Neurochemistry, The Sahlgrenska Academy,
University of Gothenburg, Gothenburg, Sweden
Department of Neurodegenerative Disease, Dementia
Research Centre, UCL Institute of Neurology,
London, UK
michael.scholl@neuro.gu.se
e-mail:
its primary function. In this respect, the activity
of tau is mediated by its degree of phosphorylation, with tau containing 2–3mol of phosphate
per mol of the protein under physiological conditions [3]. Hyperphosphorylation of tau, however,
decreases its ability to bind to microtubules [4]
resulting in an increase in its cytosolic levels [5].
Following a shift from axonal to somatodendritic
compartments, hyperphosphorylated tau, being
an amyloid, then self-assembles into, among
other aggregates, paired helical laments (PHFs)
[6] and, subsequently neurobrillary tangles
(NFTs). The accumulation of these pathological
forms of tau is a common feature of several neurodegenerative disorders collectively referred to
as tauopathies, of which Alzheimer’s disease
(AD) is the most common. Recently, high afnity
positron emission tomography (PET) tracers
selective for tau aggregates were introduced,
enabling the visualization, mapping, and quantication of tau pathology invivo [
7].
The challenges inherent to imaging tau notwithstanding, considerable progress has been
made over the past years with respect to the
development of tau selective PET tracers. Though
the rst PET tracer capable of binding tau aggregates—2-(1-(6-[(2-18F-fluoroethyl)(methyl)
amino]-2-naphthyl)ethylidene) malononitrile
(18F-FDDNP), a tracer with nanomolar afnity
for amyloid-β shown also to bind to NFTs [8]—
was rst reported nearly 20years ago, the development of tracers selective and specic for tau is
© 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_13
235
236
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A. Leuzy et al.
a comparatively recent development. Initial tracers include 18F-THK5317, 18F-THK5351,
18
F-ortaucipir (also known as 18F-AV1451 and
18
F-T-807), and 11C-PBB3. Used extensively in
research studies, these compounds are now properties, including 18F-MK-6240, 18F-RO948 (previously referred to as 18F-RO69558948),
18
F-PI-2620, 18F-GTP1, 18F-PM-PBB3, 18FJNJ64349311 (18F-JNJ311), and its derivative
18
F-JNJ-067 [7].
13.1.1 Synthesis
Given the number of tau PET tracers under development covered in this chapter, specics regarding synthesis strategies for all of these will not be
covered. For 18F-ortaucipir, the by far most used
tau tracer to date, several alternative methods for
synthesis have been suggested and subsequently
optimized, including synthesis from the N-Bocprotected nitro precursor [9], which eliminated
the need for the reduction of the nitro precursor
prior to purication that the original report
required to facilitate purication of 18F-ortaucipir
[10]. Holt etal. demonstrated 18F-uorination of
N-Boc-protected trimethylammonium precursor
by microwave irradiation [11] and recently an
optimized fully automated synthesis of
18
F-ortaucipir was developed which uses an
unmodied LIGAND Lab FXFN synthesis module [12]. As novel compounds become more
used, similar optimization efforts will surely follow as has recently been the case for
18
F-MK-
6240 [13].
13.1.2 Pharmacokinetics
Initial tau tracers have been subject to extensive
characterization using in vitro autoradiography
and tau immunostaining, on both parafn and
frozen AD brain tissue. Flortaucipir, THK5117,
THK5351, and PBB3 (with the absence of labels
reecting the use of different approaches—unlabeled as well as 11C, 18F, and 3H labeled—across
studies) have all been shown to bind to neurobrillary tangles (intracellular and extracellular
“ghost tangle” variants) as well as to neuritic
plaques [
14]. Contradictory ndings, however,
have been reported for pretangles. In vitro binding assays using tau brils or human brain
homogenates and brain sections have shown current tau tracers to have favorable binding properties (nanomolar range) and point to several
binding sites. In vitro autoradiography studies in
non-AD tauopathies [15, 16], most involving
direct comparison with tau immunostaining, suggest that PBB3 and tracers of the THK family
may be better able to detect non-AD tau, relative
to ortaucipir.
Binding of tau PET tracers to non-tau targets
(the so-called off-target binding) stands as an
important and as yet unresolved challenge. Offtarget binding of 18F-ortaucipir, 11C-PBB3, and
the 18F-THK compounds has been reported predominantly in the choroid plexus, the basal ganglia, and the meninges [17]. While iron and
neuromelanin have been proposed to underlie the
signal from the basal ganglia [18, 19], binding in
the choroid plexus has been attributed to the presence of calcications, “on-target” binding to
tangle- like structures (Biondi ring tangles), and
melanocytes [17]. Other studies point to offtarget binding to monoamine oxidase A (MAOA, 18F-ortaucipir) [20] and B (MAO-B,
18
F-ortaucipir, and 18F-THK5317) [21]. Though
novel tau tracers appear to be less affected, uptake
in the ethmoid sinus, clivus, the meninges, and
substantia nigra has been reported with 18F-MK6240 and 18F-RO948in a small sample of AD
patients and older cognitively unimpaired adults
[22, 23].
Initial studies of the different tau PET tracers
have shown that binding kinetics of tracer binding to tau are well described by the two-tissue
compartment model (2TCM) for most tracers
[24–26]. While compartmental modeling provides detailed insights into the binding characteristics, it is sensitive to noise and requires arterial
blood sampling as well as long, fully dynamic
PET acquisitions. More robust estimates of tracer
retention can be achieved for the tau tracers using
the plasma input Logan graphical model and—
alleviating the need for arterial sampling—the
reference input Logan graphical model using
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