Translational Molecular Imaging of Prostate Cancer

Abstract

Prostate cancer is a heterogeneous disease, and its management is now evolving to become more personalized and to incorporate new targeted therapies. With these new changes comes a demand for molecular imaging techniques that can not only detect disease but also assess biology and treatment response. This review article summarizes current molecular imaging approaches in prostate cancer (e.g. ^99mTc bone scintigraphy and ¹⁸F-fluorodeoxyglucose positron emission tomography) and highlights emerging clinical and preclinical imaging agents, with an emphasis on mechanism and clinical application. Emerging agents at various stages of clinical translation include radiolabeled analogs of lipid, amino acid, and nucleoside metabolism, as well as agents more specifically targeting prostate cancer biomarkers including androgen receptor, prostate-specific membrane antigen and others. We also highlight new techniques and targeted contrast agents for magnetic resonance imaging and spectroscopy. For all these imaging techniques, a growing and important unmet need is for well-designed prospective clinical trials to establish clear indications with clinical benefit in prostate cancer.

Introduction

Prostate cancer is the most common cancer in American men, with an estimated annual incidence of 241,740 and mortality of 28,170 in 2012 [1]. The disease spectrum is extremely broad, ranging from indolent asymptomatic disease to aggressive metastatic disease. For this reason, clinical management is individualized based on risk factors including stage, serum prostate-specific antigen (PSA) level, and pathologic Gleason score, as outlined in the risk stratification schema of the National Comprehensive Cancer Network [2, 3]. Local treatment options include radical prostatectomy, external beam radiation, and brachytherapy with radioactive seed implantation. However, recent data increasingly supports the management of very low risk disease with active surveillance, as these patients are often over-treated [4, 5].

For patients with intermediate to high-risk or metastatic disease, the mainstay of systemic treatment is androgen deprivation therapy. Until recently, there were no effective treatment options for castrate-resistant prostate cancer (CRPC), but in the past 5 years several agents have shown a significant survival benefit in CRPC and join docetaxel [6] as therapeutic options in this clinical scenario. These include the anti-microtubule agent cabazitaxel [7], the oral CYP17 inhibitor abiraterone (that decreases testosterone production) [8, 9], the androgen receptor antagonist enzalutamide [10], and the autologous cancer vaccine sipuleucel-T [11]. With these new agents, the landscape for treatment of metastatic prostate cancer is changing rapidly.

The trend toward more personalized care and development of new combination therapies for prostate cancer raises a demand for more specialized biomarkers and imaging techniques. Serum PSA testing remains the standard of care for detection and monitoring, but it has been limited by a low specificity (20-40%) that is only partially improved by adaptations such as PSA density, PSA velocity, and free PSA [12]. Likewise, imaging techniques such as computed tomography (CT) and ^99mTc-based bone scintigraphy have been limited by low accuracy, low-specificity, and inability to detect nodal disease for bone scintigraphy [13]. There is particular clinical need for improved imaging sensitivity for detection of micrometastatic disease during initial workup and for discrimination of locoregional versus distant disease in the setting of PSA relapse. Improved intraprostatic imaging could also influence local treatment choices and/or treatment planning. However, beyond the need for improved detection of disease, there is a challenge for molecular imaging to assess disease biology (e.g. indolent vs. aggressive) and treatment response (e.g. to androgen-deprivation and new CRPC treatments). This review article will summarize the many existing and emerging molecular imaging techniques for prostate cancer, with particular emphasis on their potential for mechanism-based and personalized approaches to disease management.

Imaging prostate cancer: present

Traditional prostate cancer anatomic imaging techniques include transrectal ultrasound (TRUS), CT and magnetic resonance imaging (MRI) [14]. TRUS has become an essential tool for guidance of interventions such as prostate biopsies and radioactive seed placement by anatomical imaging of the prostate gland but has a limited role for detection of prostate cancer [15]. CT is commonly used for initial staging of intermediate to high-risk disease, to evaluate for pelvic lymphadenopathy and gross extraprostatic disease extension. However, its sensitivity for detection of nodal metastases is only about 35% [13]. T2-weighted endorectal MRI has shown superior soft tissue resolution compared to CT for evaluating local tumor extent, especially with the use of an endorectal coil. MRI has many potential applications in prostate cancer, including initial staging, biopsy guidance, surgical planning, radiation planning, and restaging after PSA relapse [16]. However, it has not yet become widely accepted, partly due to unclear indications and high inter-observer variability.

At large referral centers with expert radiologists, multiparametric MRI is increasingly being utilized with diffusion-weighted imaging (DWI), MR spectroscopic imaging (MRSI) and/or dynamic contrast enhancement (DCE-MRI). DWI represents the functional environment of water in tissue and the cellular status of normal and pathologic tissue and therefore is an indicator for characterization and differentiation of benign versus malignant lesions [17]. MRSI can improve prostate cancer specificity and assess tumor aggressiveness by detecting metabolic signatures characteristic of disease. In particular, the ratio of choline plus creatine to citrate in prostate voxels has demonstrated a positive predictive value (PPV) of 90% in combination with MRI [18]. On DCE-MRI, prostate tumors show early enhancement and washout, and this technique can further improve specificity and tumor localization. Multiparametric MRI may be especially valuable for characterization of intraprostatic lesions in patients managed with active surveillance and in patients with PSA relapse after radiation [19, 20].

Prostate cancer most frequently metastasizes to the bone with a predominantly osteoblastic (sclerotic) pathogenesis. Therefore, the mainstay of imaging for advanced prostate cancer is ^99mTc-labeled biphosphonate (e.g. ^99mTc-methylene diphosphonate [MDP]) bone scintigraphy, which is based on the incorporation of biphosphonate analogue into hydroxyapatite crystals and collagen matrix. This molecular imaging technique is used for initial staging of intermediate to high-risk disease and for restaging after PSA relapse. It has high sensitivity and the ability to survey the entire skeleton with a simple planar scan [13]. However, it has limited specificity and is not sensitive enough to detect micrometastases. Single-photon-emission-tomography (SPECT) and SPECT/CT have been shown to improve the sensitivity and reduce the number of equivocal reports for detection of bone metastases in prostate cancer [21, 22]. Quantitative analysis using the bone scan index (BSI) has recently been shown to be prognostic for survival, and BSI is also under investigation for assessment of treatment response [23, 24].

Images of bone metastases on positron-emission-tomography (PET) may be achieved with ¹⁸F-sodium fluoride which is also incorporated into hydroxyapatite crystals in bone. ¹⁸F-NaF PET has recently demonstrated higher sensitivity than ^99mTc bone scan or SPECT for prostate cancer bone metastases, and incorporation of bone findings from CT with PET/CT provides improved specificity [21]. In a limited study, whole-body DWI MRI demonstrated a higher specificity but lower sensitivity compared with ¹⁸F-NaF PET/CT [25]. Another advantage of ¹⁸F-NaF PET is the shorter scan time compared to bone scans. ¹⁸F-NaF was approved by the FDA in 1972 for use with planar gamma scanners but had poor resolution compared to ^99mTc-MDP. However, the recent positive PET results and widespread availability of PET have prompted the initiation of a large ongoing prospective study of ¹⁸F-NaF by the National Oncology PET Registry (NOPR) through the Centers for Medicare and Medicaid Services (CMS) (http://www.cancerpetregistry.org/).

¹⁸F-FDG PET has been of limited use in prostate cancer due to the relatively low uptake in the setting of biochemical recurrence or castrate-dependent disease and the nonspecific uptake of ¹⁸F-FDG in prostatitis or benign prostatic hypertrophy (BPH) for primary disease. However, there is evidence that ¹⁸F-FDG PET may be useful for restaging after PSA relapse and for assessment of treatment response in CRPC [26-29]. In particular, ¹⁸F-FDG PET is most useful for evaluating lymph node and bone metastases in patients with PSA > 2.4 ng/mL and PSA velocity > 1.3 ng/mL/yr [28]. In a recent study by Meirelles et al., ¹⁸F-FDG PET showed higher sensitivity than ^99mTc bone scan for bone metastases due to CRPC [30].

A number of molecular imaging agents have been developed to target the biomarker, prostate-specific membrane antigen (PSMA), an integral membrane glycoprotein that is highly upregulated in prostate cancer. A mouse monoclonal antibody against PSMA, ¹¹¹In-capromab pendetide (ProstaScint™), was approved by the FDA in 1996 and initially showed potential for restaging after PSA relapse. However, this agent repeatedly failed in the clinical setting, likely due to poor pharmacokinetics and failure to reach its target epitope on the intracellular portion of PSMA [31-33]. Other emerging techniques based on PSMA are quite promising and will be discussed below.

Imaging prostate cancer: experimental and near-term future

An expanding number of molecular imaging agents for prostate cancer are currently being tested in humans, and we anticipate that several of these will gather widespread clinical application in the near future. In broad categories, these probes include: lipid components (¹¹C/¹⁸F-choline and ¹¹C-acetate), amino acids (¹¹C-methionine, ¹⁸F-FACBC leucine analog, and ¹⁸F-glutamine), nucleoside analogs (¹⁸F-FMAU thymidine analog), molecular targeting agents (¹⁸F-FDHT for androgen receptor; ¹¹¹In-J591, ¹⁸F-DCFBC and others for PSMA), and macrophage targeting agents (lymphotropic nanoparticles for MRI). We will address each of these categories with special emphasis on mechanism and potential clinical application (summarized in Table 1). However, for all of these agents, the greatest need is for prospective, controlled clinical trials to establish clear indications for use in prostate cancer.

Table 1.

Current molecular imaging agents in prostate cancer (in clinical use or trials).

Agent	Technique	Half-life	Mechanism	Application
18F-FDG	PET	110 min	Glucose analog	PSA relapse
99mTc-MDP	Planar/ SPECT	6 hr	Bone targeting (hydroxyapatite)	Bone metastases
18F-NaF	PET	110 min	Bone targeting (hydroxyapatite)	Bone metastases
111In-capromab pendetide	SPECT	67 hr	PSMA binding (antibody)	PSA relapse
11C/18F -choline	PET	20 min/ 110 min	Lipid metabolism agent	PSA relapse
11C-acetate	PET	20 min	Lipid metabolism agent	PSA relapse
18F-FACBC	PET	110 min	L-leucine amino acid analog	TBD
11C-methionine	PET	20 min	Amino acid	Initial staging
18F-FMAU	PET	110 min	Thymidine analog	TBD
18F-FDHT	PET	110 min	Androgen receptor binding (testosterone-based)	Treatment response
111In-J591	SPECT	67 hr	PSMA binding (antibody)	TBD
18F-DCFBC	PET	110 min	PSMA binding (urea-based)	TBD
68Ga-PSMA	PET	68 min	PSMA binding (urea-based)	TBD
Ferumoxtran	MRI	N/A	Macrophage targeting (nanoparticles)	Lymph node metastases

Lipid metabolism agents

The development of ¹⁸F-choline has recently been expertly reviewed by Bauman et al. and will therefore only be summarized here [34]. Briefly, prostate cancer cells have been shown to have increased fatty acid metabolism with up-regulation and increased activity of lipogenic enzymes [35]. ¹¹C/¹⁸F-choline and ¹¹C-acetate in prostate cancer have been associated with choline kinase [36, 37] and fatty acid synthase [38], respectively. The major advantage of ¹⁸F-choline is its longer half-life compared to ¹¹C-choline (110 min vs. 20 min). However, ¹⁸F-choline has more urinary excretion with bladder accumulation. These agents are not ideal for initial staging due to false positives in prostatitis and BPH and false negatives in small (<5 mm) or necrotic tumors [39]. However, they have shown promise for restaging after PSA relapse, with high sensitivity for local recurrence, nodal metastases and bone metastases [40-43]. A recent study by Giovacchini et al. showed that ¹¹C-choline uptake correlates with PSA velocity and doubling time in the setting of PSA relapse [44]. Furthermore, Souvatzoglou and Rigatti have demonstrated the potential application of ¹¹C-choline for personalized image-guided salvage radiation or lymph node dissection [45, 46]. The utility of ¹¹C-choline after PSA relapse was further highlighted by its recent FDA approval for this indication at the Mayo Clinic. Like ¹¹C-choline, ¹¹C-acetate may be best used for restaging, and studies have shown enhanced sensitivity compared to ¹⁸F-FDG [47, 48]. A direct comparison of ¹¹C-acetate and ¹¹C-choline by Kotzerke et al. showed no clear clinical differences between these agents [49].

Amino acid analogs

The amino acids leucine, methionine, and glutamine are effectively taken up by many tumors due to increased amino acid transport and metabolism. The most promising of these agents for prostate cancer imaging has been anti-1-amino-3-¹⁸F-fluorocyclobutane-1-carboxylic acid (anti-¹⁸F-FACBC), an L-leucine analog with excellent tumor uptake and minimal urinary excretion. This probe has shown early clinical success in imaging primary and recurrent disease in the prostate, pelvic lymph nodes and bone, with improved sensitivity compared to ¹¹¹In-capromab pendetide (Figure 1) [50-52]. Another amino acid, ¹¹C-methionine, has recently shown potential for initial evaluation of low and high grade primary prostate tumors and for guidance of prostate biopsies in patients with elevated PSA and multiple negative biopsies [53, 54]. Finally, glutamine metabolism is upregulated in many tumors, and ¹⁸F-labeled glutamine analogs are now emerging for imaging prostate cancer [55].

Figure 1.

Axial anti-¹⁸F-FACBC PET (A) and PET/CT (B) images in a 67-y-old patient with PSA relapse show intense activity in the left external iliac nodes (black arrow). In the same patient, axial ¹¹¹In-capromab pendetide SPECT (C) and SPECT/CT (D) images demonstrate no significant activity in this region (white arrow). Reproduced with permission from Schuster et al [52].

Nucleoside analogs

The thymidine analogs ¹⁸F-2′-fluoro-5-methyl-1-beta-D-arabinofuranosyl uracil (FMAU) and ¹⁸F-3′-fluoro-3′ deoxythymidine (FLT) are biomarkers of cellular proliferation. ¹⁸FFMAU has been evaluated in a phase 0 study of multiple cancers and showed uptake in primary prostate cancer as well as bone metastases [56]. Furthermore, preclinical studies have demonstrated that ¹⁸F-FMAU uptake is associated with androgen signaling, with increased uptake in castrated animals [57]. ¹⁸F-FLT has shown promise in many cancers for evaluation of early treatment response, and it is currently being tested in prostate cancer clinical trials after preclinical success in prostate models [58].

Molecular targeting agents

Direct imaging of androgen receptors in prostate cancer is now possible using ¹⁸F-16β-fluoro-5α-dihydrotestosterone (FDHT), and receptor binding specificity has been proven in humans by blocking with flutamide or testosterone [59, 60]. ¹⁸F-FDHT has shown a 78% tumor localization rate in patients with metastatic disease, but it is most unique in its successful application for PET pharmacodynamics in a phase I-II trial of the new androgen receptor antagonist enzalutamide for CRPC [60, 61]. In this study by Scher et al., PET imaging of 22 patients showed decreased ¹⁸F-FDHT binding after 4 weeks of enzalutamide therapy (at all doses) compared to baseline (Figure 2) [61]. This serves as a proof of principle for the application of molecular imaging agents for prostate cancer drug development and for assessment of individual treatment response [26, 59, 60].

Figure 2.

¹⁸F-FDHT PET images at baseline (A) and after 4 weeks of treatment with enzalutamide (B). The sagittal and coronal images were taken 1 h after administration of ¹⁸F-FDHT. After four weeks, they show a reduction in ¹⁸F-FDHT accumulation in tumor within the vertebrae, compared with the cardiac and aortic blood pool. Reproduced with permission from Scher et al [61].

As noted above, PSMA is a well-characterized biomarker that has been recognized as a molecular imaging target in prostate cancer for many years. PSMA expression is associated with aggressive disease biology, and it is also upregulated by androgen deprivation [62-64]. Though clinical results with ¹¹¹In-capromab pendetide have been disappointing, other promising PSMA probes are now entering clinical trials, including antibodies and small molecules. The monoclonal antibody J591, developed by Bander et al., targets the extracellular portion of PSMA and has been labeled with several PET and SPECT radionuclides [65-67]. In early phase studies, ¹¹¹In-J591 has shown accurate detection of prostate cancer bone and soft tissue metastases, as well as uptake in the tumor neovasculature of many solid tumors (where PSMA is also expressed) [65, 68]. The PET agent ⁸⁹Zr-desferrioxamine B (DFO)-J591 has shown excellent tumor uptake and retention in preclinical models and is now entering clinical trials [69]. Figure 3 shows specific uptake of ⁸⁹Zr-DFO-J591 in PSMA-positive LNCaP xenografts (tumor-to-muscle ratio of 26:1 at 144 hr) but not in PSMA-negative PC3 xenografts (tumor-to-muscle ratio of 5:1 at 144 hr) [69]. Other antibody-based agents in preclinical development include ⁶⁴Cu-J591, which has been used to demonstrate PSMA upregulation after androgen blockade, ⁶⁴Cu-3/A12, a monoclonal antibody to the extracellular portion of PSMA, and ⁸⁹Zr-(DFO)-7E11, a monoclonal antibody to the intracellular portion of PSMA [70-72].

Figure 3.

Temporal PET images of ⁸⁹Zr-DFO-J591 in mice bearing LNCaP xenografts (PSMA-positive, A) or PC-3 xenografts (PSMA-negative, B). Axial and coronal planar images at the center of the tumors show PSMA-specific uptake and retention of ⁸⁹Zr-DFO-J591. Mean tumor-to-muscle ratios and upper thresholds of scale are shown. Reproduced with permission from Holland et al [69].

Our group and others have developed small molecules targeting PSMA in order to improve tumor uptake and clearance from non-target sites [73, 74]. A low-molecular-weight, urea-based inhibitor of PSMA, ¹⁸F-N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-fluorobenzyl-L-cysteine (¹⁸F-DCFBC) has now been evaluated in a phase 0 trial for progressive metastatic prostate cancer. Bone and soft tissue metastases were successfully visualized by PET, including probable early bone lesions that were not seen on CT or ^99mTc-MDP bone scan (Figure 4) [75]. A second-generation low-molecular weight ¹⁸F-fluorine labeled PSMA targeting agent, 2-(3-[1-Carboxy-5-[(6-[¹⁸F]fluoro-pyridine-3-carbonyl)-amino]-pentyl]-ureido)-pentanedioic acid (¹⁸F-DCFPyL), has also been developed with preclinical studies demonstrating high tumor to background ratio at two hours post-injection of 39.4 ± 5.4 percent injected dose per gram of tissue (%ID/g) evident within the PSMA expressing tumor xenografts [76]. A PSMA-targeting SPECT agent ^99mTc-trofolastat, developed by Molecular Insight Pharmaceuticals, has also shown rapid uptake in human bone and soft tissue metastases and is now in phase II trials [77]. We have also synthesized a ^99mTc-radiolabeled PSMA agent, which in preclinical studies demonstrates tumor-to-background ratio of 44:1 at 120 min post-injection [78]. In addition, another urea-based inhibitor, Glu-NH-CO-NH-Lys-(Ahx)-[⁶⁸Ga(HBED-CC)] (⁶⁸Ga-PSMA), was recently tested in 37 prostate cancer patients and showed a median tumor-to-background ratio of 28:1 at 3 hours post-injection [79, 80]. Other urea-based agents with even higher binding affinities are in preclinical development [81].

Figure 4.

¹⁸F-DCFBC PET images in a patient with progressive metastatic prostate cancer. An area of focal ¹⁸F-DCFBC uptake in the L4 vertebral body on PET and fused PET/CT (thick arrows, A) showed no correlative abnormality on CT (thin arrow, A) or bone scan (arrow, B). Reproduced with permission from Cho et al [75].

Macrophage targeting agents

A class of functional MRI contrast agents has been developed to target macrophages within lymph nodes, a technique termed lymphotropic nanoparticle-enhanced MRI (LNMRI) or MR lymphangiography. These agents are composed of inert ultra-small supraparamagnetic iron oxide (USPIO) particles (e.g. ferumoxtran) that are phagocytosed by macrophages and decrease T2-weighted signal in non-tumor areas. They have shown excellent sensitivity and specificity for pelvic nodal metastases measuring at least 5 mm [82]. Indeed, a prospective multicenter study of 375 intermediate to high-risk patients confirmed that LN-MRI had significantly higher sensitivity and negative predictive value for detection of nodal metastases compared to CT [83]. This technique could be quite valuable for surgical or radiation treatment planning, as omission of pelvic nodal dissection and/or irradiation could significantly reduce toxicity.

Imaging prostate cancer: new compounds

There are many new compounds under investigation for imaging prostate cancer and, as expected, most are highly specific molecular targeting agents. This trend is consistent with the changing clinical and experimental landscape of prostate cancer, moving toward a more mechanism-based approach to this heterogeneous disease. In the following section, we highlight recent preclinical studies, particularly focusing on those published in the past few years (summarized in Table 2).

Table 2.

Future molecular imaging agents in prostate cancer (in preclinical testing).

Agent	Technique	Half-life	Mechanism/ Target
18F-FLT	PET	110 min	Thymidine analog
89Zr-(DFO)-J591	PET	78 hr	PSMA (antibody)
64Cu-J591	PET	13 hr	PSMA (antibody)
99mTc-trofolastat	SPECT	6 hr	PSMA (small molecule)
89Zr-(DFO)-5A10	PET	78 hr	free PSA (antibody)
111In-DOTA- ZIGF1R:4551	SPECT	67 hr	Insulin-like growth factor receptor (Affibody)
99mTc-bombesin	SPECT	6 hr	Gastrin-releasing peptide receptor (small molecule)
64Cu-TP3939	PET	13 hr	Vasoactive pituitary adenylate cyclase- activating peptide receptor (small molecule)
64Cu-DOTA- EpCAM mAb	PET	13 hr	Epithelial cellular adhesion molecule (antibody)
131I-NM404	SPECT	8 d	Phospholipid ether
M13-SBP-MNP	MRI	N/A	Tumor matrix glycoproteins (bacteriophage with nanoparticles and peptide)
Gd-DOTA-CLT1	MRI	N/A	Fibrin-fibronectin (small molecule)
Hyperpolarized 13C-pyruvate/lactate	MRSI	N/A	Metabolite analog

New compounds for PET or SPECT

A large variety of molecular targets are now being explored for imaging prostate cancer, including tumor receptors and other specific biomarkers. A free PSA antibody (5A10) conjugated with ⁸⁹Zr-(DFO) has been used in preclinical CRPC models to measure androgen receptor-dependent changes in tumor PSA expression [84]. This technique has the potential to measure treatment response to anti-androgens and other therapies. A group in Sweden has recently focused on the insulin-like growth factor-1 receptor (IGF-1R), which is involved in androgen independence and is an emerging drug target. Their Affibody-based agent ¹¹¹In-DOTA-ZIGF1R:4551 showed IGF-1R-specific uptake in DU-145 xenografts with a tumor-to-blood ratio of 3:1 at 8 hours [85]. A series of ^99mTc-labeled bombesin compounds have been developed to target the gastrin-releasing peptide receptor, which is overexpressed in many cancers, and they have shown tumor-to-muscle ratios of up to 24:1 at 24 hours in PC3 xenografts [86]. The vasoactive pituitary adenylate cyclase-activating peptide receptor-1 (VPAC1) is expressed in all prostate cancers, and a VPAC1-targeting peptide probe ⁶⁴Cu-TP3939 has shown uptake in PC3 xenografts with a tumor-to-muscle ratio of 6:1 at 24 hours [87]. Hall et al. recently developed a monoclonal antibody to the epithelial cellular adhesion molecule EpCAM (expressed in many cancers) that is dual labeled with ⁶⁴Cu-DOTA and IRDye 800CW. In an orthotopic PC3 xenograft model, they demonstrated 87% accuracy for identification of nodal metastases [88]. Counsell et al. has developed multiple radiolabeled versions of phospholipid ethers, which are abundant in a variety of tumors, and they have shown tumor uptake of up to 18% of the injected dose per gram at day 5 for ¹³¹I-NM404 in PC3 xenografts [89, 90].

New compounds for MRI or MRSI

Several groups have recently targeted extracellular matrix proteins to improve MRI contrast enhancement in prostate cancer models. Ghosh et al. used a novel M13 bacteriophage as a carrier for multiple iron oxide nanoparticles and a peptide targeting the tumor matrix glycoprotein SPARC (M13-SBP-MNP). They showed excellent nanoparticle delivery and MRI contrast in prostate cancer xenograft models [91]. Another group used a small molecule approach, targeting fibrin-fibronectin complexes with the cyclic peptide CLT1 conjugated to Gd-DOTA. They showed high binding specificity and improved MRI contrast compared to non-targeted Gd-DOTA in an orthotopic PC3 model [92].

Hyperpolarized ¹³C can be used as a contrast agent for MRI or MRSI, as it briefly retains its nuclear polarization after injection. Using a fast MRSI technique with ¹³C-labeled pyruvate and lactate in the transgenic adenocarcinoma of mouse prostate (TRAMP) model, Chen et al. effectively detected prostate tumors and correlated ¹³C-lactate uptake with tumor grade [93, 94]. In addition, Yaligar et al. recently demonstrated that increased ¹³C-lactate correlated with tumor aggression in prostate cancer models [95]. Therefore, this technique shows promise for not only detecting tumors but also assessing their biology.

Conclusion

As the management of prostate cancer becomes more personalized and new treatments become available, there is increasing clinical demand for molecular imaging beyond ^99mTc bone scintigraphy and ¹⁸F-FDG PET. In this review, we have highlighted the great number and variety of emerging molecular imaging agents for prostate cancer. Many of these have been tested in early phase clinical trials and have shown excellent potential for detection of primary and metastatic disease. We are particularly encouraged by several recent studies that demonstrate proof of principle for the use of molecular imaging to assess specific tumor biology or treatment response in prostate cancer. However, larger controlled trials will be necessary to establish clear clinical indications for these agents.