REVIEWS

Current use of PSMA–PET in prostate

cancer management
Tobias Maurer1, Matthias Eiber2, Markus Schwaiger2 and Jürgen E. Gschwend1
Abstract | Currently, the findings of imaging procedures used for detection or staging of prostate
cancer depend on morphology of lymph nodes or bone metabolism and do not always meet
diagnostic needs. Prostate-specific membrane antigen (PSMA), a transmembrane protein that
has considerable overexpression on most prostate cancer cells, has gained increasing interest as
a target molecule for imaging. To date, several small compounds for labelling PSMA have been
developed and are currently being investigated as imaging probes for PET with the 68Ga-labelled
PSMA inhibitor Glu‑NH‑CO‑NH‑Lys(Ahx)-HBED‑CC being the most widely studied agent.
68
Ga-PSMA–PET imaging in combination with multiparametric MRI (mpMRI) might provide
additional molecular information on cancer localization within the prostate. In patients with
primary prostate cancer of intermediate-risk to high-risk, PSMA-based imaging has been
reported to improve detection of metastatic disease compared with CT or mpMRI, rendering
additional cross-sectional imaging or bone scintigraphy unnecessary. Furthermore, in patients
with biochemically recurrent prostate cancer, use of 68Ga-PSMA–PET imaging has been shown
to increase detection of metastatic sites, even at low serum PSA values, compared with
conventional imaging or PET examination with different tracers. Thus, although current
knowledge is still limited and derived mostly from retrospective series, PSMA-based imaging
holds great promise to improve prostate cancer management.

With an estimated incidence of 1,111,700 cases per results, the level of serum PSA and histological findings
year and an estimated mortality of 307,000 men per year, following analysis of the biopsy sample3,11. In patients
prostate cancer is one of the most prevalent cancers with intermediate-risk to high-risk prostate cancer, CT
worldwide1. In western countries prostate cancer is the or MRI of the lower abdomen accompanied by bone
most common cancer in men, with roughly 758,700 new scintigraphy are currently recommended in guidelines
cases diagnosed per year, and it is the third most com- from the European Association of Urology3 and the
mon cause of cancer-associated mortality in men1. Thus, National Comprehensive Cancer Network11. In patients
accurate diagnosis and staging of prostate cancer is of with recurrent and/or metastatic prostate cancer, bone
upmost importance. scintigraphy, CT and MRI are recommended for detect-
According to current guidelines, diagnosis of prostate ing tumours or evaluating treatment responses3,11. Newer
cancer is most commonly made by sonography-guided imaging modalities that have been investigated for use in
needle biopsy2,3. In men in whom prostate cancer is sus- prostate cancer diagnosis and staging include PET with
pected but histological findings are negative, MRI has choline-based tracers or fluorodeoxyglucose12,13; how-
1
Department of Urology,
Technische Universität
evolved as the standard imaging procedure3,4. Suspicious ever, despite these advances in imaging, these procedures
München. lesions on MRI facilitate histological confirmation of still have considerable limitations and are not always able
2
Department of Nuclear prostate cancer by aiding targeted sampling in subse- to meet diagnostic needs as they do not always reliably
Medicine, Technische quent biopsies5,6. However, a certain portion of pros- identify local recurrence, lymph node involvement or
Universität München,
tate cancer lesions might still be missed using MRI7–10. visceral metastases3,13–19.
Klinikum rechts der Isar,
Ismaninger Strasse 22, In these patients, additional molecular information The use of PET probes targeting prostate-specific
81671 Munich, Germany. obtained by PET imaging with prostate-cancer-specific membrane antigen (PSMA, also known as glutamate
Correspondence to T.M. tracers is desirable. carboxypeptidase 2) for imaging prostate cancer has
[email protected] After diagnosis, patients with histologically con- gained increasing interest and shows great promise
doi:10.1038/nrurol.2016.26 firmed prostate cancer are stratified to distinct risk for improving the management of patients with pros-
Published online 23 Feb 2016 groups according to their digital-rectal examination tate cancer20. This Review will provide an overview of

226 | APRIL 2016 | VOLUME 13 www.nature.com/nrurol

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 REVIEWS

of prostate cancer owing to its biological characteristics,

Key points
including: consider­able (100‑fold to 1,000‑fold) over-
• Prostate-specific membrane antigen (PSMA) is a promising and specific target for expression on the cell membrane of nearly all prostatic
prostate cancer imaging cancer cells compared with normal nontarget expression
• PSMA–PET imaging can add molecular information to multiparametric MRI and, (on normal prostate epithelial cells, in the small intes-
therefore, delineate suspicious lesions for targeted biopsies, especially in patients tine, renal tubular cells and the salivary glands)35,47–50,
whose biopsy samples are tumour-negative increased expression in advanced-stage and castration-­
• PSMA–PET imaging shows increased specificity and sensitivity compared with resistant prostate cancers — several studies exist show-
current standard imaging (CT, MRI and bone scintigraphy) in patients with primary ing that PSMA expression levels increase according to
intermediate-risk or high-risk prostate cancer the stage and grade of the tumour35,47,51 — potentially
• PSMA–PET imaging improves detection of metastatic lesions even at low serum PSA enabling PSMA imaging to be used for prognosis, a large
values in biochemically recurrent prostate cancer extracellular domain enabling targeting using anti­bodies
• Enhanced detection of prostate cancer lesions might enable improved and a cytoplasmic domain containing an internaliza-
patient-tailored therapy planning and, therefore, lead to improved therapy outcomes tion motif that results in internal­ization and endosomal
recycling, which increases the deposition of conjugated
radiometals into the cell with subsequent improvement
current knowledge regarding PSMA targeting and ima­ of both imaging and thera­peutic efficacy52,53. This lat-
ging with PSMA ligands, and will highlight the possi- ter feature makes PSMA an attractive target, especially
ble clinical application of PSMA-based imaging to the for developing small-­molecule radiopharmaceuticals
­management of patients with prostate cancer. (PSMA inhibitors) that are typically cleared quickly
from the bloodstream and have low background activ-
PSMA as a target in prostate cancer ity54. However, the degree of internalization has not been
PSMA is a type II transmembrane protein (FIG. 1), which fully investigated for all available PSMA inhibitors.
has a 19‑amino-acid intracellular portion, a 24‑amino-­ Since the 1980s, efforts have been made to target spe-
acid transmembrane portion and a 707‑­amino-­acid cific regions of the intracellular or extracellular domain
extracellular portion21. The PSMA gene (also known as of PSMA with monoclonal antibodies labelled with dif-
FOLH1) is located on the short arm of chromosome 11 ferent isotopes for nuclear medicine imaging55 (FIG. 1).
in a region that is not commonly deleted in patients with To date, only one radiolabelled anti-PSMA antibody
prostate cancer22. PSMA expression and localization in (ProstaScint®, Jazz Pharmaceuticals, USA) targeting an
the normal human prostate is associated with the cyto- intracellular epitope (7E11) of PSMA has been approved
plasm and apical side of the epithelium surrounding by the FDA56. J591, a monoclonal antibody targeting the
prostatic ducts but not basal epithelium, neuro­endocrine extracellular domain of PSMA, localizes to viable tumour
or stromal cells23. Cytoplasmic PSMA is truncated at the cells and has shown effective image contrast in clinical
N‑terminus and is called PSMʹ, it has no folate-hydrolase trials57. However, in general, the effectiveness of anti-
activity or capacity to hydrolyse N‑acetylaspartylglutamic bodies as diagnostic radiopharmaceuticals is limited by
acid24,25, and its function is not known. Dysplastic and/or a long circulating half-life resulting in a high unspeci­fic
neoplastic transformation of prostate tissue results in background activity and poor tumour penetrability. The
the transfer of PSMA from the apical membrane to the combination of antibodies with long-lived PET radio­
luminal surface of the ducts 26,27. The transition to isotopes (such as 89Zr) or using only single-chain frag-
androgen-­independent prostate cancer eventually leads ments (such as antibody fragments D7‑Fc and D7‑CH3)
to further PSMA expression28,29 The PSMA:PSMʹ ratio could be potential solutions to these limitations58–60.
increases as prostate tumour cells increase in Gleason
grade26. Interestingly, PSMA expression has also been PSMA ligands
reported in the tumour neo­vasculature of some solid The identification of the active substrate recognition
tumours (including colon, breast and renal cancer and site of PSMA with its structural and functional homol-
subtypes of bladder cancer) and in newly formed blood ogy to glutamate carboxypeptidase 2 (also known as
vessels30–35. PSMA is also expressed on astrocytes of the N‑acetylated-α‑linked acidic dipeptidase I) promoted
central nervous system and it is known as glutamate the development of small molecules as PSMA lig-
­carboxypeptidase 2 in these cells36,37. ands or inhibitors61,62. The recognition site contains
Consequently, this nonprostatic PSMA expression two zinc ions and is composed of two pockets, the
has led to anecdotal reports of high uptake of PSMA glutamate-­s ensing pocket (the S1ʹ pocket) and the
inhibitors in a variety of lesions that are incidentally non-­pharmacophore pocket (the S1 pocket). Most
present in patients that have undergone PSMA–PET for of the inhibitors have a zinc-binding component and
staging or restaging of prostate cancer38–43. PSMA is only glutamate or glutamate isostere, which resides in the
enzymatically active in its homodimeric form44, and is S1ʹ pocket63. PSMA inhibitors fall into three families:
made up of two monomers with intracellular, transmem- phosphorous-­based (including phosphonate, phosphate,
brane and extracellular domains45. After a ligand (such as and phosphoramidate), thiol-based and urea-based.
a small-­molecule antagonist or a specific antibody) binds Urea-based inhibitors have a high affinity for PSMA,
to PSMA, internalization occurs and it is either retained specificity for PSMA and fast and efficient internal­
in lysosomal compartments, or released into the cyto- ization in LNCaP cells54; therefore, current research into
plasm44,46. PSMA is an ideal target for molecular imaging small-­molecule PSMA inhibitors is mainly focused on

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these pharmaceutically engineered agents. The struc-

tural and functional variety of PSMA ligands and their
e
­development is reviewed elsewhere64.
Several research groups have reported the use
of small-molecule inhibitors of PSMA labelled with
123
I (REFS 65–67) , 99mTc (REFS 68,69) , 18F (REFS 70,71) , J591 antibodies
111
In ­(REFS 50,72) and 68Ga (REFS 20,54,73–76). d
The inhibitor Glu‑NH‑CO‑NH‑Lys(Ahx)- Active centre
PSMA-inhibitors
HBED‑CC (68Ga-PSMA-HBED‑CC), which was initi­
ally described by Eder et al.54 in 2012, is the most widely
used agent for PET imaging. On binding to prostate
cancer cells, internalization occurs and high accumula- c
tion of 68Ga-PSMA-HBED‑CC, even in small metasta-
ses, is observed. This agent is also rapidly cleared from
Extracellular
nontarget tissue. Physiologically, this radiotracer shows
enhanced accumulation in salivary glands, the liver, the
b Cell membrane
spleen, the small bowel and the urinary tract77. However,
hardly any uptake is observed in retro­peritoneal fatty
Intracellular
tissue, benign lymphatic tissue and bone, which are
a 7E11 antibodies
locations where prostate cancer is likely to metasta-
size35,41,77.68Ga-PSMA-HBED‑CC has become a valu-
able diagnostic agent in monitoring of both recurrent Figure 1 | The structure of prostate-specific membrane
prostate cancer and responses to therapy. N,Nʹ‑­bis[2– antigen (PSMA), its binding sitesNature Reviews
for PSMA | Urology
ligands
hydroxy‑­5-­(carboxyethyl)-­b enzyl]ethylenediamine‑­ and the most frequently used antibodies. a | The short
N,Nʹ‑diacetic acid (HBED‑CC) can easily be labelled intracellular domain containing a binding site that can be
targeted with 7E11 antibodies. b | The hydrophobic
with 68Ga at room temperature as it is an efficient 68Ga
transmembrane region. The extracellular part of PSMA
chelator with fast complexing kinetics and good stabil- consists of section c | that contains two domains of
ity78. Eder and colleagues54 described its synthesis using unknown function and proline-rich and glycine-rich regions
HBED‑CC, which is an analogue of hydroxy­b enzyl as linkers, d | that is the large catalytic domain, which
ethylenediamine (HBED). HBED is an attractive che- contains a binding site for J591 antibodies as well as the
lator for 68Ga as they form a thermodynamically stable active substrate recognition site that is being targeting by
complex74. In an initial preclinical in vivo study, PSMA- PSMA inhibitors and e | the final domain of unknown
positive LNCaP tumour xenografts were visible at 1 h function to which a helical dimerization domain is localized.
after injection and tumour:muscle and tumour:blood
uptake ratios were favourable54. Reports on the clini- (as it requires a much shorter distance to decelerate the
cal value of 68Ga-PSMA-HBED‑CC in PET imaging of positron in human tissue in comparison with 68Ga owing
recurrent and primary prostate cancer showed that it has to its low positron emission energy, resulting in higher
high detection rates compared with data from literature image resolution)86. Labelling PSMA with 18F could also
and in direct comparison with 18F-choline20,67–69,75–79. be achieved by fluorinating the HBED compound. Malik
In 2015, a different 68Ga-labelled PSMA ligand for and colleagues87 showed this approach to be successful
PET imaging, EuK-Subkff-68Ga-DOTAGA (68Ga-PSMA when they applied this agent to PSMA-positive LNCaP
Imaging & Therapy (I&T)) was introduced, which can cells; however, further preclinical and clinical studies on
also be labelled with 177Lu or 111In (REFS 50,76,79–81). the effectiveness of this agent are currently lacking.
Thus, it can serve as a theranostic agent for both imag- Besides fluorination of known compounds,
ing (68Ga) and radioguided surgery (111In) or PSMA- new, specifically 18F-labelled compounds have been
targeted endoradiotherapy (177Lu). Another theranostic reported. A first generation 18F-labelled PSMA ligand,
agent, referred to as PSMA-DKFZ‑617, was described 18
F-DCFBC, was described by Mease and colleagues88.
initially by Benešová and colleagues82, with the first stud- PSMA-positive PC‑3 PIP xenografts were clearly vis-
ies using a 68Ga-labbelled compound and reporting low ible as early as 20–30 min after injection with only
radiation exposure and very high contrast when used for faint uptake observed in the PSMA-negative PC‑3
detection of prostate cancer lesions82,83. Currently, this FLU xenografts. In a clinical study, researchers investi­
agent is being investigated for use in PSMA-targeted gated 18F-DCFBC in five patients who had radio­logi­
endoradiotherapy84,85. cal evidence of metastatic disease, and imaging with
The development of 18F-labelled PSMA compounds 18
F-DCFBC identified more suspicious lesions than bone
offers potential advances with regard to increasing the scintigraphy or CT, but whether any of these lesions
number of examinations possible, owing to a higher were false positives was not investigated89. In another
available amount of the radioisotope 18F produced by preliminary study in 13 patients with primary prostate
a cyclotron compared with 68Ga eluted from a gener- cancer, 18F-DCFBC–PET was able to reliably detect clini­
ator86. An excellent image quality is also likely, which cally significant high-grade and large-volume tumours
will result from optimized tracer doses leading to high (Gleason scores 8 and 9) with relatively low uptake in
imaging statistics and the decay properties of 18F itself benign prostatic lesions71. The disadvantage of using this

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a b c 289 Slice number: 6/20

277
255

Signal intensity
234
212
191
169
148
126
105
83 Local
62
0 29 58 87 116 145 174 203 232 261 290
Time (seconds)

d e f

Figure 2 | 68Ga-PSMA–PET–MRI of a 50‑year-old patient who had a rising serum PSA value (16 ng/ml at imaging)
and two tumour-negative previous biopsy samples. a | T2‑weighted image showing a hypointense Nature Reviews
mass | Urology
in the anterior
fibromuscular stroma with pronounced arterial enhancement. b | Typical pronounced arterial contrast enhancement
compared with the surrounding tissue. c | Intensity curve of the dynamic contrast enhanced sequence shows a typical fast
washin followed by washout in the late phase. d | Diffusion-weighted imaging demonstrates markedly restricted diffusion.
e | PET image and f | fused PET–MRI showing intense prostate-specific membrane antigen (PSMA) expression in the
corresponding region. Targeted PET–MRI fusion biopsy revealed prostate cancer with Gleason score 7 in this region.

agent lies in the considerable activity of this agent in the (DCE) and diffusion-weighted imaging (DWI), and to a
bloodstream, which could potentially interfere with the lesser extent MRI spectroscopy (termed mulitparamen-
detection of lymph-node metastases89. tric MRI (mpMRI)) — often enables a more accurate
In 2011, a second generation 18F-labelled PSMA ligand investigation of the prostate than MRI alone91–94. Prostate
18
F-DCFPyL was introduced, with favourable results for cancer lesions often appear hypointense in T2‑weighted
tissue binding in vitro and in vivo. High tumour uptake sequences, but they typically show fast influx and wash-
ratios between PSMA-positive PC3 PIP and PSMA- out of contrast material on DCE. In DWI, a reduced dif-
negative PC3 FLU xenografts were also observed70. In the fusion capacity of water molecules (reduced apparent
first clinical investigation in nine patients, 18F-DCFPyL diffusion coefficient (ADC)) owing to densely packed
showed very high levels of uptake in sites of putative tumour cells as well as shifted choline and citrate metab-
metastatic disease, as well as in primary tumours90. Very olism on MRI spectroscopy have been observed27,95–98.
low blood pool activity was observed and the conspicu- Furthermore, mpMRI can be used to detect aggres-
ousness of lesions was notably higher with 18F-DCFPyL sive prostate cancer lesions with greater sensitivity and
than with the first-generation radiotracer 18F-DCFBC ­specificity than MRI alone99–101.
making it a promising agent. Data from a first prelim- The introduction of whole-body hybrid PET–MRI
inary study comparing 68Ga-PSMA-HBED‑CC with scanners with simultaneous acquisition and exact ana-
18
F-DCFPyL showed that 18F-DCFPyL had a better tomical coregistration of PET imaging and mpMRI
tumour:background accumulation ratio, and additional has enabled functional and molecular information to
lesions plausible for metastases were detected in three of be combined102,103. PSMA ligands, as prostate-cancer-­
the 14 patients when 18F-DCFPyL was used86. specific PET tracers, might help to visualize and delin-
eate cancerous lesions more accurately within the
Local detection prostate than choline derivatives, which are currently
MRI has emerged as the imaging technique of choice for the most widely used PET tracers14,104,105 (FIG. 2). The
detection of prostate cancer after inconclusive or nega- high lesion:background ratio of the 68Ga-PSMA–PET
tive biopsy findings, as well as for local staging regard- signal of suspicious lesions, as well as the information
ing capsule penetration or seminal vesicle involvement3. obtained from mpMRI, enables histological confirma-
T2‑weighted MRI sequences enable anatomical resolu- tion of prostate cancer using targeted fusion biopsies,
tion of the zonal anatomy of the prostate and the delin- especially in patients with previously negative findings
eation of suspicious areas. The addition of functional on biopsy-­sample analyses, as has been shown in pre-
MRI sequences — namely dynamic-contrast-enhanced liminary studies106,107. In slight contrast to these findings,

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a b c

Figure 3 | 68Ga-PSMA–PET–CT of a 52‑year-old patient with primary prostate cancer (serum PSA value of
19 ng/ml and Gleason score 7 at biopsy). a | Contrast enhanced CT shows a small lymph node Nature Reviews |to
(6 mm) adjacent Urology
the
right internal iliac artery. b | PET and c | fused PET–CT images demonstrate intense prostate-specific membrane antigen
(PSMA) expression in this lymph node. Radical prostatectomy and lymphadenectomy revealed a lymph node metastasis
in the corresponding template field.

in an initial series of 13 patients Rowe et al.71 reported a can help to distinguish between metastatic and normal
decreased sensitivity of 18F-DCFBC–PET for the detec- lymph nodes112–114. However, a broad overlap in DWI
tion of prostate cancer lesions compared with mpMRI; measurements between malignant and benign lymph
however, the specificity for detection of high-grade and nodes has been noted113. In general, the performance
more clinically significant disease was increased71. In of CT and MRI for lymph node staging is not signifi-
addition, interpretation of mpMRI might be hindered by cantly different, as demonstrated in a meta-analysis that
changes after biopsy sampling such as local haemorrhage included 24 studies108. In this meta-analysis, the pooled
or inflammation, whereas interpretation of 68Ga-PSMA– sensitivity was 42% and 39% and the pooled specificity
PET does not seem to be influenced by biopsy104. Thus, was 82% and 82%, for CT and MRI, respectively111. The
the combination of 68Ga-PSMA–PET with mpMRI authors concluded that both modalities are insufficient
might improve rates of prostate cancer detection and at to reliably identify lymphatic spread, which in turn could
the same time avoid the use of unnecessary biopsy pro- jeopardize further treatment success.
cedures. However, not all prostate cancers have substan- With the introduction of PET imaging and its com-
tial PSMA overexpression (~10% of primary ­prostate bination with CT or MRI hopes were raised for an
cancers do not overexpress PSMA)105,108. increased detection rate, especially of small meta­static
lymph nodes, owing to the addition of metabolic infor-
Primary staging mation to morpho­logical cross-­sectional imaging. Several
The goal of primary staging is to detect metastatic spread different PET tracers, including 18F-fluordeoxyglucose,
to the first landing sites — primarily lymph nodes, bone 11
C-choline, 18 F-choline, 18 F-fluorocholine and
or other, visceral, organs. In low-risk prostate cancer 11
C-acetate, have been studied in patients with pros-
metastatic spread is very unlikely; consequently, current tate cancer15,115–118. To date, the most evidence exists for
guidelines suggest staging examinations should only be choline-­based tracers. However, after the first enthusi-
undertaken for intermediate-risk to high-risk prostate astic reports119,120, a systematic review and meta-­analysis
cancer3,11. For evaluation of spread to lymph nodes and conducted in 2013 revealed a only moderate pooled
visceral organs CT or MRI are used, whereas bone scin- sensitivity of 49.2%, at the same time demonstrating a
tigraphy is recommended for excluding bony metastases, high specificity of 95%, for the detection of metastatic
although data from an initial study indicated that whole- lymph nodes in prostate cancer16. Data from other studies
body MRI might be a superior modality for detecting showed sensitivities ranging from 33 to 45%, but con-
metastasis to bone109. Naturally, staging has considerable firmed high specificities of over 95% in larger patient
influence on further treatment choices (such as radical cohorts121,122. Despite its high specificity, current guide-
prostatectomy, radiotherapy or palliative systemic treat- lines do not recommend PET imaging for lymph node
ment and the extent of pelvic lymph node dissection staging of patients with primary prostate cancer with
during surgery or planning of the radiation field, and choline-based tracers as detection of metastatic lymph
also the consideration of multimodal therapy), exact nodes is still hampered by the moderate sensitivity of
staging assists in making the most appropriate choice. this technique3.
Evaluation of lymph nodes using CT or MRI solely The use of PSMA ligands for PET imaging might par-
depends on morphological information, and meta- tially overcome this limitation. In a retrospective analysis
static lymph nodes are mainly detected on the basis of of 130 consecutive patients with primary intermediate-­
increased size. However, almost 80% of metastatic lymph risk to high-risk prostate cancer who underwent radi­
nodes in prostate cancer are smaller than the threshold cal prostatectomy with template pelvic lymph node
size of 8 mm and, therefore, cannot be detected using dissection, our group observed a sensitivity of 65.9%
morphological imaging110,111. The use of DWI in MRI and specificity of 98.9% for lymph node staging with

230 | APRIL 2016 | VOLUME 13 www.nature.com/nrurol

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a b Staging of recurrent prostate cancer

Localization of prostate cancer lesions is a major challenge
in patients with biochemical recurrence. The differenti­
ation of localized disease and metastatic spread is of great
importance for further disease management, especially at
low serum PSA values. For example, salvage radiotherapy
in patients whose cancer recurs after radical prostatectomy
is most effective at serum PSA values <0.5 ng/ml126,127.
Thus, radiotherapy should be initiated as early as possi-
ble in these circumstances3. Conventional bone scintig-
raphy or CT imaging show very limited detection rates
for metastatic prostate cancer lesions at low serum PSA
values at the time of biochemi­cal recurrence after cura-
tive treatment128; therefore, in most guidelines, ima­ging
is recommended for patients who are symptomatic or
c d whose serum PSA levels are >10 ng/ml3,17. PET imaging
with choline-based tracers has been found to improve
staging and enhance detection of recurrent prostate can-
cer15. However, these tracers still lack the ability to iden-
tify smaller lesions or prostate cancer without increased
metabolic activity — especially at low PSA velocity or
serum PSA values <2 ng/ml18. Thus, PET imaging with
choline-based tra­cers is not usually recommended at early
stages of recurrence. Considering the fact that biochemi­
cal relapse is already expected in patients after radical
prostatectomy with serum PSA levels >0.2 ng/ml, imaging
techniques with improved s­ ensitivity are highly desired.
In 2015, reports from two studies, with large patient
cohorts, investigating 68Ga-PSMA–PET were published
Figure 4 | 68Ga-PSMA–PET–CT of a 73‑year-old patient withNature recurrent prostate
Reviews | Urology addressing the issue of staging of recurrent prostate can-
cancer after radical prostatectomy (initial Gleason score 9) and local salvage cer73,129. Afshar-Oromieh and colleagues77 investi­gated
radiotherapy. Upper images are from a staging 68Ga-PSMA-PET–CT examination at a the performance of this tracer in 319 patients with recur-
serum PSA value of 3.6 ng/ml and the lower images are from a restaging examination rent prostate cancer (226 had received radical prostatec-
six months later at a serum PSA value of 1.8 ng/ml. a | Fused PET–CT demonstrates an
tomy) and a median serum PSA value of 4.6 ng/ml. At
intense uptake in the thoracic spine suspicious for a bone metastasis. b | The
corresponding CT reveals no morphological correlation. c | Fused PET–CT images, least one lesion typical of prostate cancer was found in
6 months later, shows no substantial uptake of 68Ga-PSMA in the lesion after external ~83% of patients. The authors demonstrated detection
radiotherapy. d | CT shows a new sclerosis indicating post-therapeutic changes. rates of 50% for serum PSA values <0.5 ng/ml and 58%
PSMA, prostate-specific membrane antigen. for serum PSA values from 0.5–1 ng/ml. In 42 patients,
histological confirmation of lesions could be obtained.
Of note, in these patients, all lesions that had a positive
68
Ga-PSMA–PET108 (FIG. 3). Of note, the patients with 68
Ga-PSMA–PET signal had histologically confirmed
tumour-positive lymph nodes that were missed by metastatic prostate cancer (n = 98); however, 29 lymph
PSMA-PET presented with PSMA-negative primary nodes and one local relapse was missed. Tumour
tumours or had micrometastases in single lymph Gleason score and/or androgen deprivation therapy did
nodes. In line with our findings, other groups have also not significantly influence detection rates.
reported a high specificity of lymph node detection Data from our group support these findings. In a
with use of 68Ga-PSMA–PET (REFS 75,120), although, homogeneous consecutive cohort of 248 patients with
small metastatic lymph nodes might still be missed. biochemical recurrence after radical prostatectomy who
Furthermore, bony and visceral lesions of prostate can- had a mean serum PSA value of 1.99 ng/ml, 89.5% of
cer that might not be detectable using standard imaging patients had suspicious lesions detected by 68Ga-PSMA–
can be visualized by 68Ga-PSMA–PET (REFS 123–125). PET–CT. For serum PSA values of 0.2–<0.5 ng/ml, 0.5–
Thus, especially in patients with high-risk prostate can- <1 ng/ml, 1–<2 ng/ml and ≥2 ng/ml, detection rates were
cer, 68Ga-PSMA–PET in combination with CT or MRI 57.9%, 72.7%, 93.0% and 96.8%, respectively129. These
could enable a complete staging of the local tumour, rates are substantially higher than those reported for
lymph node involvement, bone metastases and organ choline-based PET tracers, which have reported detec-
metastases with increased accuracy within one single tion rates of between 19% and 36% at serum PSA lev-
examination, superseding current standard imaging els <1.5 ng/ml18,130–132. These enhanced detection rates
and possibly improving treatment planning125. However, can be mainly attributed to information obtained from
published data on primary staging with PSMA ligands is 68
Ga-PSMA–PET, as opposed to diagnostic CT, as it
still very limited and further research is needed before exclusively showed suspicious findings not evident
drawing robust conclusions. on diagnostic CT in 32.7% of patients and provided

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REVIEWS

a b of 223Ra-dichloride). However, a major limitation of all

these studies is the lack of systematic histological con-
firmation in most patients. Furthermore, follow‑up ima­
ging was only available in a subset of patients. Thus, the
results of these studies have to be considered with caution,
although, in the meantime PSMA ligands have been suc-
cessfully applied in intraoperative tracking of metastatic
prostate cancer lesions, underlining the high sensitivity
and specificity of PSMA ligands50. Even small metastatic
soft-tissue prostate cancer deposits could be localized and
removed using P ­ SMA-radioguided surgery for salvage
procedures (FIG. 6).

Impediments to clinical application

Despite the potential advantages of PSMA-based ima­
ging for patients with prostate cancer, several limitations
have to be considered. Currently, PSMA-based imaging is
not globally available, mainly owing to regulatory issues.
Special national regulations that only allow the applica-
tion of new drugs (which have not been finally approved)
under certain restrictions mean that only a few centres in
several European, South American and Asian countries,
as well as Australia can use these novel tracers outside
Figure 5 | Imaging of 65‑year-old patient with prostate cancer and diffuse of clinical trials. Some centres in the USA and Europe
bone metastases. a | Bone scintigraphy demonstrates multipleNature Reviews | Urology
bone metastases use PSMA-based imaging within clinical trials (such
predominantly in the pelvis and ribs. b | Corresponding maximum-intensity projection
as NCT02611882, NCT02282137, NCT02190279, and
of 68Ga-PSMA–PET shows considerably more bone metastases than bone scintigraphy.
EudraCT 2014‑004758‑33)134–137. However, a rapid spread
PSMA, prostate-specific membrane antigen.
of this new technology has been observed in countries
where application of PSMA-ligands for imaging is permit-
information about additional involved anatomical ted. The issue of reimbursement by health-care providers,
regions in 24.6% (FIG. 4). In comparison, morphological which mostly does not cover PSMA-based imaging as it is
CT alone revealed suspicious lesions that were not appar- still considered experimental, is another limitation. Thus,
ent when assessed by 68Ga‑PSMA-PET in 1.2% of patients the design and execution of prospective trials are a high
and additional involved anatomical regions in 6.9%129. priority so that evidence required to enable implementa-
The combination of 68Ga-PSMA–PET to MRI instead of tion of this promising imaging t­ echnology into clinical
CT might be able to improve detection rates in patients guidelines is obtained.
with very low serum PSA values (<0.5 ng/ml). In these
patients, the diagnostic accuracy might be improved Conclusions
by combination with mpMRI, mainly owing to the fact Imaging with PSMA–PET has the potential to influ-
that mpMRI has a higher detection efficacy for locally ence the management of patients with prostate cancer13.
recurrent tumours than CT133. Compared with absolute Optimizing the labelling of PSMA inhibitors might also
serum PSA value, the effects of PSA velocity and PSA be of interest as initial reports suggest that 18F-labelled
doubling time on detection rates were less pronounced. PSMA inhibitors might be advantageous, owing to their
A high PSA velocity (P = 0.0532) and short PSA doubling increased availability, and the possibility that they will
time (P = 0.2971) showed a tendency for increased detec- have a positive influence on image resolution.
tion rates129. Increased detection efficacy in patients with PSMA–PET imaging might improve detection, local-
Gleason scores >8 was observed in this patient cohort, in ization or exclusion of cancerous foci within the prostate.
contrast to findings from the study by Afshar-Oromieh In this setting, combination of PSMA–PET with mpMRI
and colleagues73. instead of CT is highly preferable, owing to the excellent
Direct comparison of 18F-fluoromethylcholine–PET anatomical and zonal resolution of the prostate obtained
with 68Ga-PSMA–PET in 37 patients with recurrent by T2‑weighted MRI sequences. Furthermore, functional
prostate cancer demonstrated that 68Ga-PSMA–PET is the MRI sequences (mainly DWI and DCE sequences) can be
superior modality for lesion detection74. All lesions visible used to detect and localize suspicious lesions. In combined
by 18F-fluoromethylcholine were detected by 68Ga-PSMA– hybrid PET–MRI, PSMA–PET provides additional molec-
PET and this tracer also revealed suspicious lesions in six ular information by direct detection and localization of
patients that use of 18F-fluoromethylcholine–PET missed. PSMA-positive tissue, which might be useful — especially
Data from initial studies reveal that 68Ga-PSMA–PET in patients who have had several biopsy samples taken,
has a higher detection efficacy than bone scintigraphy which have proven negative on analysis, where detection
for describing the whole extent of bone involvement124,125 or exclusion of prostate cancer is warranted. In these cases,
(FIG. 5). This improved detection rate might be of relevance the information obtained from PSMA–PET–MRI can be
when monitoring is desired (such as before and after use used to perform targeted biopsies and, therefore, increase

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a b c

Figure 6 | 68Ga-PSMA–PET–CT of a 74‑year-old patient with recurrent prostate cancer (initial Gleason score 7)
after radical prostatectomy and local salvage radiotherapy with rising serum PSA value Nature (1. 76 ng/ml at| the
Reviews Urology
time of assessment). a | Contrast-enhanced CT shows a mass in the area of the former left seminal vesicle having residual
tissue, reactive fibrosis or recurrent disease. b | PET and c | fused PET–CT images demonstrate intense 68Ga-PSMA uptake,
indicative of a locally recurrent tumour. Salvage PSMA-radioguided surgery revealed soft-tissue poorly differentiated
adenocarcinoma of the prostate (Gleason score 7) including a seminal vesicle with a cribriform carcinoma. PSMA,
prostate-specific membrane antigen.

the diagnostic performance of prostate biopsy sample undergone radical prostatectomy, PSMA–PET improves
analysis. However, the availability of combined PET– detection of metastatic prostate cancer compared with
MRI and the high costs associated with this approach conventional cross-sectional imaging or bone scintig-
are limiting factors that preclude the widespread use of raphy. Furthermore, it increases the detection of lesions
this technology. even at serum PSA values <0.5 ng/ml compared with
Evaluation of metastatic spread to lymph nodes, bone conventional imaging or PET examination with dif-
or visceral organs in patients with primary intermediate-­ ferent tracers. As salvage radiotherapy is most effective
risk or high-risk prostate cancer might be improved by at low serum PSA values, PSMA–PET imaging could
PSMA–PET imaging. In these patients PSMA–PET–MRI be used to optimize radiotherapy planning by defining
or PSMA–PET–CT enables a whole staging procedure the target lesions or areas that are most appropriate for
to be performed in one single examination, rendering boost radiotherapy.
further cross-sectional imaging or bone scintigraphy PSMA–PET imaging could also facilitate new sal-
unnecessary. Furthermore, data from currently published vage treatment options by identifying patients with
studies suggest that 68Ga-PSMA–PET imaging increases oligometa­static disease that are suitable for PSMA-
diagnostic accuracy for primary staging of patients with radioguided surgery. The high uptake of PSMA-inhibitors
prostate cancer. Thus, the results of PSMA–PET ima­ in castration-­resistant prostate cancer means that these
ging might i­nfluence treatment selection and modify ligands are good candidates for facilitating guided endo-
therapy approaches. radiotherapy in patients with metastatic prostate cancer.
Currently, recurrent prostate cancer is the main indi- Hereby, PSMA inhibitors could potentially be used as
cation for the use of PSMA–PET and the majority of theranostic agents in patients with metastasic prostate
published data focus on this setting. In patients who have cancer, to ­visualize and treat these lesions at the same time.

1. Torre, L. A. et al. Global cancer statistics, 2012. 8. Reisaeter, L. A. et al. 1.5‑T multiparametric MRI using 14. Souvatzoglou, M. et al. The sensitivity of [11C]choline
CA Cancer J. Clin. 65, 87–108 (2015). PI‑RADS: a region by region analysis to localize the PET/CT to localize prostate cancer depends on the
2. American Urological Association. Guideline for the index-tumor of prostate cancer in patients undergoing tumor configuration. Clin. Cancer Res. 17,
management of clinically localized prostate cancer prostatectomy. Acta Radiol. 56, 500–511 (2015). 3751–3759 (2011).
(2007). [online], http://www.auanet.org/education/ 9. Hoeks, C. M. et al. Transition zone prostate cancer: 15. Brogsitter, C., Zophel, K. & Kotzerke, J. 18F‑choline,
guidelines/prostate-cancer.cfm (2007). detection and localization with 3‑T multiparametric 11
C‑choline and 11C‑acetate PET/CT: comparative
3. European Association of Urology. Guidelines on MR imaging. Radiology 266, 207–217 (2013). analysis for imaging prostate cancer patients.
Prostate Cancer. http://uroweb.org/guideline/prostate- 10. Schimmoller, L. et al. MR‑sequences for prostate Eur. J. Nucl. Med. Mol. Imaging 40, S18–S27
cancer/ (2015). cancer diagnostics: validation based on the PI‑RADS (2013).
4. Barentsz, J. O. et al. ESUR prostate MR guidelines scoring system and targeted MR‑guided in‑bore 16. Evangelista, L., Guttilla, A., Zattoni, F., Muzzio, P. C.
2012. Eur. Radiol. 22, 746–757 (2012). biopsy. Eur. Radiol. 24, 2582–2589 (2014). & Zattoni, F. Utility of choline positron emission
5. Baco, E. et al. Magnetic resonance imaging-transectal 11. National Comprehensive Cancer Network. Prostate tomography/computed tomography for lymph node
ultrasound image-fusion biopsies accurately cancer. [online], http://www.nccn.org/patients/ involvement identification in intermediate- to high-
characterize the index tumor: correlation with step- guidelines/prostate/files/assets/common/downloads/ risk prostate cancer: a systematic literature review
sectioned radical prostatectomy specimens in 135 files/prostate.pdf (2015). and meta-analysis. Eur. Urol. 63, 1040–1048 (2013).
patients. Eur. Urol. 67, 787–794 (2015). 12. Umbehr, M. H., Muntener, M., Hany, T., Sulser, T. 17. Beresford, M. J., Gillatt, D., Benson, R. J. &
6. Valerio, M. et al. Detection of clinically significant & Bachmann, L. M. The role of 11C‑choline and Ajithkumar, T. A systematic review of the role of
prostate cancer using magnetic resonance imaging- 18F‑fluorocholine positron emission tomography (PET) imaging before salvage radiotherapy for post-
ultrasound fusion targeted biopsy: a systematic review. and PET/CT in prostate cancer: a systematic review prostatectomy biochemical recurrence. Clin. Oncol.
Eur. Urol. 68, 8–19 (2015). and meta-analysis. Eur. Urol. 64, 106–117 (2013). (R. Coll. Radiol.) 22, 46–55 (2010).
7. Dianat, S. S., Carter, H. B. & Macura, K. J. Performance 13. Yu, C. Y., Desai, B., Ji, L., Groshen, S. & Jadvar, H. 18. Krause, B. J. et al. The detection rate of [11C]choline-
of multiparametric magnetic resonance imaging in the Comparative performance of PET tracers in PET/CT depends on the serum PSA-value in patients
evaluation and management of clinically low-risk biochemical recurrence of prostate cancer: a critical with biochemical recurrence of prostate cancer.
prostate cancer. Urol. Oncol. 32, 39.e1–39.e10 analysis of literature. Am. J. Nucl. Med. Mol. Imaging Eur. J. Nucl. Med. Mol. Imaging 35, 18–23
(2014). 4, 580–601 (2014). (2008).

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r
i
g
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t
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REVIEWS

19. Schoder, H. et al. 2-[18F]fluoro-2‑deoxyglucose HBED‑CC PET/CT. Eur. J. Nucl. Med. Mol. Imaging 42, 65. Foss, C. A. et al. Radiolabeled small-molecule ligands
positron emission tomography for the detection of 1622–1623 (2015). for prostate-specific membrane antigen: in vivo
disease in patients with prostate-specific antigen 41. Krohn, T. et al. [68Ga]PSMA-HBED uptake mimicking imaging in experimental models of prostate cancer.
relapse after radical prostatectomy. Clin. Cancer Res. lymph node metastasis in coeliac ganglia: an Clin. Cancer Res. 11, 4022–4028 (2005).
11, 4761–4769 (2005). important pitfall in clinical practice. Eur. J. Nucl. Med. 66. Hillier, S. M. et al. Preclinical evaluation of novel
20. Afshar-Oromieh, A., Haberkorn, U., Eder, M., Mol. Imaging 42, 210–214 (2015). glutamate-urea-lysine analogues that target prostate-
Eisenhut, M. & Zechmann, C. M. [68Ga]gallium-labelled 42. Schwenck, J. et al. In vivo visualization of prostate- specific membrane antigen as molecular imaging
PSMA ligand as superior PET tracer for the diagnosis specific membrane antigen in glioblastoma. pharmaceuticals for prostate cancer. Cancer Res. 69,
of prostate cancer: comparison with 18F‑FECH. Eur. J. Nucl. Med. Mol. Imaging 42, 170–171 (2015). 6932–6940 (2009).
Eur. J. Nuclear Med. Mol. Imaging 39, 1085–1086 43. Rischpler, C., Maurer, T., Schwaiger, M. & Eiber, M. 67. Maresca, K. P. et al. A series of halogenated
(2012). Intense PSMA-expression using 68Ga‑PSMA PET/CT heterodimeric inhibitors of prostate specific membrane
21. Leek, J. et al. Prostate-specific membrane antigen: in a paravertebral schwannoma mimicking prostate antigen (PSMA) as radiolabeled probes for targeting
evidence for the existence of a second related human cancer metastasis. Eur. J. Nucl. Med. Mol. Imaging prostate cancer. J. Med. Chem. 52, 347–357 (2009).
gene. Br. J. Cancer 72, 583–588 (1995). 43, 193–194 (2016). 68. Kularatne, S. A., Zhou, Z., Yang, J., Post, C. B. &
22. O’Keefe, D. S. et al. Mapping, genomic organization 44. Ghosh, A. & Heston, W. D. W. Tumor target prostate Low, P. S. Design, synthesis, and preclinical evaluation
and promoter analysis of the human prostate-specific specific membrane antigen (PSMA) and its regulation of prostate-specific membrane antigen targeted
membrane antigen gene. Biochim. Biophys. Acta in prostate cancer. J. Cell. Biochem. 91, 528–539 99m
Tc‑radioimaging agents. Mol. Pharm. 6, 790–800
1443, 113–127 (1998). (2004). (2009).
23. DeMarzo, A. M., Nelson, W. G., Isaacs, W. B. & 45. Schülke, N. et al. The homodimer of prostate- 69. Lu, G. et al. Synthesis and SAR of 99mTc/Re‑labeled
Epstein, J. I. Pathological and molecular aspects of specific membrane antigen is a functional target small molecule prostate specific membrane antigen
prostate cancer. Lancet 361, 955–964 (2003). for cancer therapy. Proc. Natl Acad. Sci. USA 100, inhibitors with novel polar chelates. Bioorg. Med.
24. Grauer, L. S. et al. Identification, purification, and 12590–12595 (2003). Chem. Lett. 23, 1557–1563 (2013).
subcellular localization of prostate-specific membrane 46. Commandeur, L. C. & Parsons, J. R. Degradation of 70. Chen, Y. et al. 2-(3-{1‑carboxy‑5-[(6-[18F]fluoro-
antigen PSMʹ protein in the LNCaP prostatic halogenated aromatic compounds. Biodegradation 1, pyridine-3‑carbonyl)-amino]-pentyl}-ureido)-
carcinoma cell line. Cancer Res. 58, 4787–4789 207–220 (1990). pentanedioic acid, [18F]DCFPyL, a PSMA-based PET
(1998). 47. Bostwick, D. G., Pacelli, A., Blute, M., Roche, P. & imaging agent for prostate cancer. Clin. Cancer Res.
25. Heston, W. D. Characterization and glutamyl Murphy, G. P. Prostate specific membrane antigen 17, 7645–7653 (2011).
preferring carboxypeptidase function of prostate expression in prostatic intraepithelial neoplasia and 71. Rowe, S. P. et al. 18F‑DCFBC PET/CT for PSMA-based
specific membrane antigen: a novel folate hydrolase. adenocarcinoma: a study of 184 cases. Cancer 82, detection and characterization of primary prostate
Urology 49, 104–112 (1997). 2256–2261 (1998). cancer. J. Nucl. Med. 56, 1003–1010 (2015).
26. Huang, E., Teh, B. S., Mody, D. R., Carpenter, L. S. & 48. Mannweiler, S. et al. Heterogeneity of prostate-specific 72. Banerjee, S. R. et al. A modular strategy to prepare
Butler, E. B. Prostate adenocarcinoma presenting with membrane antigen (PSMA) expression in prostate multivalent inhibitors of prostate-specific membrane
inguinal lymphadenopathy. Urology 61, 463 (2003). carcinoma with distant metastasis. Pathol. Oncol. Res. antigen (PSMA). Oncotarget 2, 1244–1253 (2011).
27. Wu, L. M., Xu, J. R., Ye, Y. Q., Lu, Q. & Hu, J. N. 15, 167–172 (2009). 73. Afshar-Oromieh, A. et al. The diagnostic value of
The clinical value of diffusion-weighted imaging in 49. Troyer, J. K., Beckett, M. L. & Wright, G. L. PET/CT imaging with the 68Ga‑labelled PSMA ligand
combination with T2‑weighted imaging in diagnosing Detection and characterization of the prostate-specific HBED‑CC in the diagnosis of recurrent prostate cancer.
prostate carcinoma: a systematic review and meta- membrane antigen (PSMA) in tissue extracts and body Eur. J. Nucl. Med. Mol. Imaging 42, 197–209 (2015).
analysis. AJR Am. J. Roentgenol. 199, 103–110 fluids. Int. J. Cancer. 62, 552–558 (1995). 74. Afshar-Oromieh, A. et al. Comparison of PET imaging
(2012). 50. Maurer, T. et al. Prostate-specific membrane antigen- with a 68Ga‑labelled PSMA ligand and 18F‑choline-
28. Birtle, A. J. et al. Tumour markers for managing men radioguided surgery for metastatic lymph nodes in based PET/CT for the diagnosis of recurrent prostate
who present with metastatic prostate cancer and prostate cancer. Eur. Urol. 68, 530–534 (2015). cancer. Eur. J. Nucl. Med. Mol. Imaging 41, 11–20
serum prostate-specific antigen levels of <10 ng/mL. 51. Chang, S. S. Overview of prostate-specific membrane (2014).
BJU Int. 96, 303–307 (2005). antigen. Rev. Urol. 6, S13–S18 (2004). 75. Afshar-Oromieh, A. et al. PET/MRI with a 68Ga‑PSMA
29. Evans, M. J. et al. Noninvasive measurement of 52. Rajasekaran, S. A. et al. A novel cytoplasmic tail ligand for the detection of prostate cancer. Eur. J. Nucl.
androgen receptor signaling with a positron-emitting MXXXL motif mediates the internalization of prostate- Med. Mol. Imaging 40, 1629–1630 (2013).
radiopharmaceutical that targets prostate-specific specific membrane antigen. Mol. Biol. Cell 14, 76. Weineisen, M., Simecek, J., Schottelius, M.,
membrane antigen. Proc. Natl Acad. Sci. USA 108, 4835–4845 (2003). Schwaiger, M. & Wester, H.‑J. Synthesis and preclinical
9578–9582 (2011). 53. Liu, H. et al. Constitutive and antibody-induced evaluation of DOTAGA-conjugated PSMA ligands for
30. Chang, S. S. et al. Prostate-specific membrane antigen internalization of prostate-specific membrane antigen. functional imaging and endoradiotherapy of prostate
is produced in tumor-associated neovasculature. Cancer Res. 58, 4055–4060 (1998). cancer. EJNMMI Res. 4, 63 (2014).
Clin. Cancer Res. 5, 2674–2681 (1999). 54. Eder, M. et al. 68Ga‑complex lipophilicity and the 77. Afshar-Oromieh, A. et al. PET imaging with a [68Ga]
31. Chang, S. S. et al. Five different anti-prostate-specific targeting property of a urea-based PSMA inhibitor for gallium-labelled PSMA ligand for the diagnosis of
membrane antigen (PSMA) antibodies confirm PSMA PET imaging. Bioconjug. Chem. 23, 688–697 (2012). prostate cancer: biodistribution in humans and first
expression in tumor-associated neovasculature. 55. Ghosh, A. & Heston, W. D. Tumor target prostate evaluation of tumour lesions. Eur. J. Nucl. Med. Mol.
Cancer Res. 59, 3192–3198 (1999). specific membrane antigen (PSMA) and its regulation Imaging 40, 486–495 (2013).
32. Chang, S. S., Reuter, V. E., Heston, W. D. & in prostate cancer. J. Cell. Biochem. 91, 528–539 78. Roesch, F. & Riss, P. J. The renaissance of the
Gaudin, P. B. Metastatic renal cell carcinoma (2004). 68
Ge/68Ga radionuclide generator initiates new
neovasculature expresses prostate-specific membrane 56. Troyer, J. K., Beckett, M. L. & Wright, G. L. Location developments in 68Ga radiopharmaceutical chemistry.
antigen. Urology 57, 801–805 (2001). of prostate-specific membrane antigen in the LNCaP Curr. Top. Med. Chem. 10, 1633–1668 (2010).
33. Haffner, M. C. et al. Prostate-specific membrane prostate carcinoma cell line. Prostate 30, 232–242 79. Schottelius, M., Wirtz, M., Eiber, M., Maurer, T. &
antigen expression in the neovasculature of gastric (1997). Wester, H. J. [111In]PSMA‑I&T: expanding the spectrum
and colorectal cancers. Hum. Pathol. 40, 1754–1761 57. Tagawa, S. T. et al. Anti-prostate-specific membrane of PSMA‑I&T applications towards SPECT and
(2009). antigen-based radioimmunotherapy for prostate radioguided surgery. EJNMMI Res. 5, 68 (2015).
34. Samplaski, M. K., Heston, W., Elson, P., Magi- cancer. Cancer 116, 1075–1083 (2010). 80. Weineisen, M. et al. 68Ga- and 177Lu‑Labeled PSMA
Galluzzi, C. & Hansel, D. E. Folate hydrolase (prostate- 58. Elsässer-Beile, U. et al. PET imaging of prostate cancer I&T: optimization of a PSMA-targeted theranostic
specific membrane [corrected] antigen) 1 expression xenografts with a highly specific antibody against the concept and first proof‑of‑concept human studies.
in bladder cancer subtypes and associated tumor prostate-specific membrane antigen. J. Nuclear Med. J. Nucl. Med. 56, 1169–1176 (2015).
neovasculature. Mod. Pathol. 24, 1521–1529 (2011). 50, 606–611 (2009). 81. Weineisen, M., Simecek, J., Schottelius, M.,
35. Silver, D. A., Pellicer, I., Fair, W. R., Heston, W. D. & 59. Holland, J. P. et al. 89Zr‑DFO‑J591 for immunoPET Schwaiger, M. & Wester, H. J. Synthesis and preclinical
Cordon-Cardo, C. Prostate-specific membrane antigen of prostate-specific membrane antigen expression evaluation of DOTAGA-conjugated PSMA ligands for
expression in normal and malignant human tissues. in vivo. J. Nucl. Med. 51, 1293–1300 (2010). functional imaging and endoradiotherapy of prostate
Clin. Cancer Res. 3, 81–85 (1997). 60. Wiehr, S. et al. Pharmacokinetics and PET imaging cancer. EJNMMI Res. 4, 63 (2014).
36. Carter, R. E., Feldman, A. R. & Coyle, J. T. Prostate- properties of two recombinant anti-PSMA antibody 82. Benešová, M. et al. Preclinical evaluation of a
specific membrane antigen is a hydrolase with fragments in comparison to their parental antibody. tailor-made DOTA-conjugated PSMA inhibitor with
substrate and pharmacologic characteristics of a Prostate 74, 743–755 (2014). optimized linker moiety for imaging and
neuropeptidase. Proc. Natl Acad. Sci. USA 93, 61. Luthi-Carter, R., Barczak, A. K., Speno, H. & endoradiotherapy of prostate cancer. J. Nucl. Med.
749–753 (1996). Coyle, J. T. Molecular characterization of human brain 56, 914–920 (2015).
37. Robinson, M. B., Blakely, R. D., Couto, R. & Coyle, J. T. N‑acetylated α-linked acidic dipeptidase (NAALADase). 83. Afshar-Oromieh, A. et al. The novel theranostic PSMA-
Hydrolysis of the brain dipeptide N‑acetyl-l‑aspartyl- J. Pharmacol. Exp. Ther. 286, 1020–1025 (1998). ligand PSMA‑617 in the diagnosis of prostate cancer
l‑glutamate. J. Biol. Chem. 262, 14498–14506 62. Tiffany, C. W., Lapidus, R. G., Merion, A., Calvin, D. C. by PET/CT: biodistribution in humans, radiation
(1987). & Slusher, B. S. Characterization of the enzymatic dosimetry and first evaluation of tumor lesions.
38. Rowe, S. P. et al. Detection of 18F‑FDG PET/CT occult activity of PSM: comparison with brain NAALADase. J. Nucl. Med. 56, 1697–1705 (2015).
lesions with 18F‑DCFPyL PET/CT in a patient with Prostate 39, 28–35 (1999). 84. Delker, A. et al. Dosimetry for Lu‑DKFZ-PSMA‑617:
metastatic renal cell carcinoma. Clin. Nucl. Med. 41, 63. Wang, H. et al. Bioisosterism of urea-based GCPII a new radiopharmaceutical for the treatment of
83–85 (2015). inhibitors: synthesis and structure–activity relationship metastatic prostate cancer. Eur. J. Nucl. Med. Mol.
39. Rowe, S. P. et al. Imaging of metastatic clear cell renal studies. Bioorg. Med. Chem. Lett. 20, 392–397 Imaging 43, 42–51 (2015).
cell carcinoma with PSMA-targeted F‑DCFPyL PET/CT. (2010). 85. Ahmadzadehfar, H. et al. Early side effects and first
Ann. Nucl. Med. 29, 877–882 (2015). 64. Mease, R. C., Foss, C. A. & Pomper, M. G. PET imaging results of radioligand therapy with 177Lu‑DKFZ‑617
40. Verburg, F. A., Krohn, T., Heinzel, A., Mottaghy, F. M. in prostate cancer: focus on prostate-specific PSMA of castrate-resistant metastatic prostate
& Behrendt, F. F. First evidence of PSMA expression in membrane antigen. Curr. Top. Med. Chem. 13, cancer: a two-centre study. EJNMMI Res. 5, 114
differentiated thyroid cancer using [68Ga]PSMA- 951–962 (2013). (2015).

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 REVIEWS

86. Dietlein, M. et al. Comparison of [18F]DCFPyL and 105. Eiber, M. et al. Simultaneous 68Ga‑PSMA HBED‑CC 123. Chakraborty, P. S., Kumar, R., Tripathi, M., Das, C. J.
[68Ga]Ga‑PSMA-HBED‑CC for PSMA-PET imaging in PET/MRI improves the localization of primary prostate & Bal, C. Detection of brain metastasis with
patients with relapsed prostate cancer. Mol. Imaging cancer. Eur. Urol. (in the press). 68
Ga‑labeled PSMA ligand PET/CT: a novel radiotracer
Biol. 17, 575–584 (2015). 106. Storz, E. et al. PSMA-PET/MRI-guided transrectal for imaging of prostate carcinoma. Clin. Nucl. Med.
87. Malik, N. et al. Radiofluorination of PSMA-HBED via fusion biopsy for the detection of prostate cancer. 40, 328–329 (2015).
Al18F2+ chelation and biological evaluations in vitro. Eur. Urol. Suppl. 14, E217 (2015). 124. Kabasakal, L. et al. Evaluation of PSMA PET/CT
Mol. Imaging Biol. 17, 777–785 (2015). 107. Zettinig, O. et al. Multimodal image-guided prostate imaging using a 68Ga‑HBED‑CC ligand in patients
88. Mease, R. C. et al. N-[N-[(S)-1,3‑Dicarboxypropyl] fusion biopsy based on automatic deformable with prostate cancer and the value of early pelvic
carbamoyl]-4-[18F]fluorobenzyl-l‑cysteine, [18F]DCFBC: registration. Int. J. Comput. Assist. Radiol. Surg. 10, imaging. Nucl. Med. Commun. 36, 582–587 (2015).
a new imaging probe for prostate cancer. Clin. Cancer 1997–2007 (2015). 125. Maurer, T. et al. Positron emission tomography/
Res. 14, 3036–3043 (2008). 108. Maurer, T. et al. Diagnostic efficacy of 68gallium-PSMA- magnetic resonance imaging with 68Gallium-labeled
89. Cho, S. Y. et al. Biodistribution, tumor detection, and PET compared to conventional imaging in lymph node ligand of prostate-specific membrane antigen:
radiation dosimetry of 18F‑DCFBC, a low-molecular- staging of of 130 consecutive patients with promising novel option in prostate cancer imaging?
weight inhibitor of prostate-specific membrane intermediate to high-risk prostate cancer. J. Urol. Int. J. Urol. 21, 1286–1288 (2014).
antigen, in patients with metastatic prostate cancer. http://dx.doi.org/10.1016/j.juro.2015.12.025 (2015). 126. Pfister, D. et al. Early salvage radiotherapy following
J. Nucl. Med. 53, 1883–1891 (2012). 109. Lecouvet, F. E. et al. Can whole-body magnetic radical prostatectomy. Eur. Urol. 65, 1034–1043
90. Szabo, Z. et al. Initial evaluation of [18F]DCFPyL for resonance imaging with diffusion-weighted imaging (2014).
prostate-specific membrane antigen (PSMA)-targeted replace Tc 99m bone scanning and computed 127. King, C. R. The timing of salvage radiotherapy
PET imaging of prostate cancer. Mol. Imaging Biol. tomography for single-step detection of metastases in after radical prostatectomy: a systematic review.
17, 565–574 (2015). patients with high-risk prostate cancer? Eur. Urol. 62, Int. J. Radiat. Oncol. Biol. Phys. 84, 104–111
91. Futterer, J. J. et al. Prostate cancer localization with 68–75 (2012). (2012).
dynamic contrast-enhanced MR imaging and proton 110. Heesakkers, R. A. et al. MRI with a lymph-node- 128. Rouviere, O., Vitry, T. & Lyonnet, D. Imaging of
MR spectroscopic imaging. Radiology 241, 449–458 specific contrast agent as an alternative to CT scan prostate cancer local recurrences: why and how?
(2006). and lymph-node dissection in patients with prostate Eur. Radiol 20, 1254–1266 (2010).
92. Lim, H. K., Kim, J. K., Kim, K. A. & Cho, K. S. Prostate cancer: a prospective multicohort study. Lancet Oncol. 129. Eiber, M. et al. Evaluation of hybrid 68Ga‑PSMA
cancer: apparent diffusion coefficient map with 9, 850–856 (2008). ligand PET/CT in 248 patients with biochemical
T2‑weighted images for detection — a multireader 111. Hovels, A. M. et al. The diagnostic accuracy of CT and recurrence after radical prostatectomy. J. Nucl. Med.
study. Radiology 250, 145–151 (2009). MRI in the staging of pelvic lymph nodes in patients 56, 668–674 (2015).
93. Sciarra, A. et al. Value of magnetic resonance with prostate cancer: a meta-analysis. Clin. Radiol. 63, 130. Castellucci, P. et al. Is there a role for 11C‑choline
spectroscopy imaging and dynamic contrast-enhanced 387–395 (2008). PET/CT in the early detection of metastatic disease in
imaging for detecting prostate cancer foci in men 112. Akduman, E. I. et al. Comparison between malignant surgically treated prostate cancer patients with a mild
with prior negative biopsy. Clin. Cancer Res. 16, and benign abdominal lymph nodes on diffusion- PSA increase <1.5 ng/ml? Eur. J. Nucl. Med. Mol.
1875–1883 (2010). weighted imaging. Acad. Radiol. 15, 641–646 Imaging 38, 55–63 (2011).
94. Tan, C. H., Wei, W., Johnson, V. & Kundra, V. Diffusion- (2008). 131. Castellucci, P. & Picchio, M. 11C‑choline PET/CT and
weighted MRI in the detection of prostate cancer: 113. Eiber, M. et al. Preliminary results for characterization PSA kinetics. Eur. J. Nucl. Med. Mol. Imaging 40,
meta-analysis. AJR Am. J. Roentgenol. 199, 822–829 of pelvic lymph nodes in patients with prostate cancer S36–S40 (2013).
(2012). by diffusion-weighted MR‑imaging. Invest. Radiol. 45, 132. Graute, V. et al. Relationship between PSA kinetics
95. Issa, B. In vivo measurement of the apparent diffusion 15–23 (2010). and [18F]fluorocholine PET/CT detection rates of
coefficient in normal and malignant prostatic tissues 114. Kim, J. K., Kim, K. A., Park, B. W., Kim, N. & Cho, K. S. recurrence in patients with prostate cancer after total
using echo-planar imaging. J. Magn. Reson. Imaging Feasibility of diffusion-weighted imaging in the prostatectomy. Eur. J. Nucl. Med. Mol. Imaging 39,
16, 196–200 (2002). differentiation of metastatic from nonmetastatic lymph 271–282 (2012).
96. Jacobs, M. A., Ouwerkerk, R., Petrowski, K. & nodes: early experience. J. Magn. Reson. Imaging 28, 133. Maurer, T. et al. PET imaging with 68Gallium-labelled
Macura, K. J. Diffusion-weighted imaging with 714–719 (2008). ligand of prostate-specific membrane antigen
apparent diffusion coefficient mapping and 115. Jadvar, H. Imaging evaluation of prostate cancer with (68Ga‑HBED-PSMA) for staging of biochemical
spectroscopy in prostate cancer. Top. Magn. Reson. 18
F‑fluorodeoxyglucose PET/CT: utility and limitations. recurrent prostate cancer after radical prostatectomy.
Imaging 19, 261–272 (2008). Eur. J. Nucl. Med. Mol. Imaging 40, S5–S10 (2013). J. Clin. Oncol. 33 (Suppl.), 5023 (2015).
97. Manenti, G. et al. In vivo measurement of the 116. Mohsen, B. et al. Application of C-11‑acetate positron- 134. US National Library of Medicine. ClinicalTrials.gov
apparent diffusion coefficient in normal and malignant emission tomography (PET) imaging in prostate [online], https://clinicaltrials.gov/ct2/show/
prostatic tissue using thin-slice echo-planar imaging. cancer: systematic review and meta-analysis of the NCT02611882 (2015).
Radiol. Med. 111, 1124–1133 (2006). literature. BJU Int. 112, 1062–1072 (2013). 135. US National Library of Medicine. ClinicalTrials.gov
98. Puech, P. et al. Dynamic contrast-enhanced-magnetic 117. Pinaquy, J. B. et al. Comparative effectiveness of [online], https://clinicaltrials.gov/ct2/show/
resonance imaging evaluation of intraprostatic [18F]-fluorocholine PET‑CT and pelvic MRI with NCT02282137 (2015).
prostate cancer: correlation with radical prostatectomy diffusion-weighted imaging for staging in patients 136. US National Library of Medicine. ClinicalTrials.gov
specimens. Urology 74, 1094–1099 (2009). with high-risk prostate cancer. Prostate 75, 323–331 [online], https://clinicaltrials.gov/ct2/show/
99. Chen, Y. J. et al. Washout gradient in dynamic (2015). NCT02190279 (2015).
contrast-enhanced MRI is associated with tumor 118. Schumacher, M. C., Radecka, E., Hellstrom, M., 137. EU Clinical Trials Register. clinicaltrialsregister.eu
aggressiveness of prostate cancer. J. Magn. Reson. Jacobsson, H. & Sundin, A. [11C]acetate positron [online], https://www.clinicaltrialsregister.eu/ctr-search/
Imaging 36, 912–919 (2012). emission tomography-computed tomography imaging trial/2014-004758-33/AT (2015).
100. Oto, A. et al. Diffusion-weighted and dynamic of prostate cancer lymph-node metastases correlated
contrast-enhanced MRI of prostate cancer: correlation with histopathological findings after extended Author contributions
of quantitative MR parameters with Gleason score and lymphadenectomy. Scand. J. Urol. 49, 35–42 (2015). T.M. and M.E. contributed equally to the manuscript,
tumor angiogenesis. AJR Am. J. Roentgenol. 197, 119. de Jong, I. J., Pruim, J., Elsinga, P. H., Vaalburg, W. researched data for and wrote the article. All authors made a
1382–1390 (2011). & Mensink, H. J. Preoperative staging of pelvic substantial contribution to discussions of content and edited
101. Yerram, N. K. et al. Low suspicion lesions on lymph nodes in prostate cancer by 11C‑choline PET. the manuscript before submission.
multiparametric magnetic resonance imaging predict J. Nucl. Med. 44, 331–335 (2003).
for the absence of high-risk prostate cancer. BJU Int. 120. Kotzerke, J. et al. Experience with carbon‑11 choline Competing interests statement
110, E783–E788 (2012). positron emission tomography in prostate carcinoma. T.M. declares a familial association with Celgene® (Celgene
102. Souvatzoglou, M. et al. PET/MR in prostate cancer: Eur. J. Nucl. Med. 27, 1415–1419 (2000). Corporation, USA); grants or funding from Acelity®
technical aspects and potential diagnostic value. 121. Beheshti, M. et al. 18F choline PET/CT in the (KCI Licensing, Inc.), Bayer® (Bayer Aktiengesellschaft,
Eur. J. Nucl. Med. Mol. Imaging 40, S79–S88 (2013). preoperative staging of prostate cancer in patients Germany) and Takeda Oncology® (Takeda Pharmaceutical
103. Souvatzoglou, M. et al. Comparison of integrated with intermediate or high risk of extracapsular Company Limited, Japan); consultation for DLR® (Deutsches
whole-body [11C]choline PET/MR with PET/CT in disease: a prospective study of 130 patients. Luft-und Raumfahrtzentrum, Germany) and honoraria from
patients with prostate cancer. Eur. J. Nucl. Med. Mol. Radiology 254, 925–933 (2010). Astellas® (Astellas US LLC, USA), Janssen Cilag (Johnson &
Imaging 40, 1486–1499 (2013). 122. Kjolhede, H. et al. 18F‑fluorocholine PET/CT compared Johnson, USA) and Sanofi® (Sanofi Corporation, France). M.E.
104. Eiber, M. et al. 68Ga‑PSMA PET/MR with with extended pelvic lymph node dissection in high- declares grants or funding from Bayer® and honoraria
multimodality image analysis for primary prostate risk prostate cancer. World J. Urol. 32, 965–970 Astellas® and Janssen Cilag. M.S. and J.E.G. declare no
cancer. Abdom. Imaging 40, 1769–1771 (2014). (2014). competing interests.

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