Mol Imaging Biol (2017) DOI: 10.1007/s11307-017-1151-1 * World Molecular Imaging Society, 2017

REVIEW ARTICLE

Prostate Cancer Theranostics Targeting Gastrin-Releasing Peptide Receptors Lucia Baratto,1 Hossein Jadvar ,2 Andrei Iagaru1 1

Department of Radiology, Stanford University, Stanford, CA, USA Department of Radiology, University of Southern California, 2250 Alcazar Street, CSC 102, Los Angeles, CA, 90033, USA

2

Abstract Gastrin-releasing peptide receptors (GRPRs), part of the bombesin (BBN) family, are aberrantly overexpressed in many cancers, including those of the breast, prostate, pancreas, and lung, and therefore present an attractive target for cancer diagnosis and therapy. Different bombesin analogs have been radiolabeled and used for imaging diagnosis, staging, evaluation of biochemical recurrence, and assessment of metastatic disease in patients with prostate cancer. Recently, interest has shifted from BBN-like receptor agonists to antagonists, because the latter does not induce adverse effects and demonstrate superior in vivo pharmacokinetics. We review the preclinical and clinical literatures on the use of GRPRs as targets for imaging and therapy of prostate cancer, with a focus on the newer developments and theranostic potential of GRPR peptides. Key words: Bombesin, GRPR, Prostate, PET, Theranostics

Introduction Prostate cancer (PC) is the most common malignancy in elderly men [1] and the second leading cause of cancer death after lung and bronchus tumors [2]. Imaging has an important role in the management of PC patients, both for diagnosis and for early identification of local or distant recurrence that occurs in 20–50 % of cases after primary therapy, depending on the stage at diagnosis [3]. Conventional imaging such as magnetic resonance (MR), computed tomography (CT), or transrectal ultrasound has limitations related to the frequently indolent biology of the disease. Their accuracy for detection of primary or recurrent PC is sub-optimal [4, 5]. Positron emission tomography (PET) is a quantitative tool for non-invasive imaging-based interrogation of the underlying tumor biology. Several promising radiotracers are either in use or under active investigation for targeting various features of PC, including glucose metabolism (2-deoxy-[18F]fluoro-D-glucose), lipogenesis (choline, acetate), androgen receptor, prostate-

Correspondence to: Hossein Jadvar; e-mail: [email protected]

specific membrane antigen (PSMA), amino acids, and gastrin-releasing peptide receptors (GRPRs). In this review article, we focus on the current status and the outlook for bombesin-related radiopharmaceuticals targeting GRPRs.

Bombesin and Gastrin-Releasing Peptide Receptors The neuropeptide bombesin (BBN) is a natural 14-amino acid peptide (Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-GlyHis-Leu-Met-NH2), which carries a carboxyl-terminal (Cterminal) carboxyamide [6]. It is analog to the mammalian gastrin-releasing peptide (GRP), which is widely distributed in both the peripheral nervous system and peripheral tissues, particularly in the gastrointestinal tract [6]. GRP fulfills its role through G protein-coupled receptors; transmembrane proteins overexpressed in a variety of human cancers, such as PC, breast, and small-cell lung cancers; and in the tumoral vessels of urinary tract cancers [7]. Bombesin and GRP share a homologous seven-amino acid-amidated C-terminus, WAVGHLM-NH2-, which is essential for high-affinity receptor-binding GRPR [8, 9].

Baratto L. et al.: Prostate Cancer Theranostics Targeting Peptide Receptors

There are four known sub-types of bombesin receptors: neuromedin B receptor (BB1r), gastrin-releasing peptide receptor (BB2r or GRPR), orphan receptor (BB3r), and amphibious receptor (BB4r) [10]. The last is found in amphibians, while the others are presented in mammalian cells. The bombesin receptor family has various physiologic functions in the gastrointestinal tract and nervous system [6]. Their pharmacological activities include the stimulation of hormone releasing, like gastrin and somatostatin, as well as the stomach and intestine smooth muscle contraction. It has been shown that bombesin/GRP significantly stimulates the growth of androgen-dependent PC cells (LNCaP) [11] as well as androgen-independent ones (PC-3 and DU-145) [12–14]. Shimoda et al. [15] demonstrated that the addition of specific anti-bombesin antibodies (ab-BMBS) to different PC cells lines (DU-145 and PC3) significantly inhibited their growth; Bologna et al. [16] reported similar results both in vitro (using antibodies against GRP in PC3 cells lines) and in vivo (testing the same antibodies in ephitelial cell strain PMU 23 derived from a primary culture of prostatic carcinoma patients). Furthermore, it has been found that bombesin increases the invasive potential and the migration ability of PC3 and LNCa PC cells [17, 18]. Several authors reported the expression of different bombesin/GRP receptors at mRNA and protein levels of human prostate adenocarcinoma specimens [19–22]. Another important characteristic of GRPR is that it is overexpressed in prostatic tumor cells, but only low levels of receptors were found on normal prostate tissues [19, 20, 23– 25]. In 2009, Ananias et al. [26] showed for the first time the presence of GRPR on lymph node metastasis in PC patients. They retrospectively analyzed patients with histologically proven lymph nodes (15 patients) and bone metastasis (17 patients) from primary PC; GRPR was seen in 85.7 and 52.9 % of lymph nodes and bone specimens, respectively. The correlation between GRPR overexpression in PC tissues and tumor grade or stage was studied by several authors, and different results were reported. Nagasaki et al. [23] demonstrated a significant positive correlation between GRPR expression and Gleason score in 51 PC patients, while no correlation was found with patients’ age, serum PSA level, pathological stage, or lymph node status. Beer et al. [24] analyzed the expression of GRPR both in benign and in malignant prostate samples from 530 PC patients. They found out a significant inverse correlation with GRPR and higher Gleason score, PSA value, and tumor size, so GRPR was more highly overexpressed in lower-grade cancer and smaller-sized tumors. A positive association between GRP expression and relapse or advanced tumor stages was reported by Constantinides et al. [27]. These discoveries resulted in an increased interest toward bombesin analogs to image and treat cancers. Because of the poor in vivo stability of GRP, considerable efforts have been made in the development of bombesin analogs for targeting

GRPR [28]. Currently, different bombesin analogs have been labeled with gamma- and positron-emitting radionuclides such as In-111 [29], Tc-99m [30–32], Ga-68 [31], F18 [33], and Cu-64 [31, 34] for visualization of GRPRexpressing tumors, as well as with cytotoxic beta- and alpha particle-emitting nuclides Y-90 [29], Lu-177 [29, 35], and Bi-212/213 [36] for targeted radionuclide therapy.

GRPR Agonists The first-generation bombesin analog radiopharmaceuticals were GRPR agonists derived from C-terminal fragments of the amphibian tetradecapeptide bombesin [37–41]. GRPR agonists have the property to be internalized when they bind to the receptors. This characteristic leads to a prolonged retention in the targeted cell and therefore was assumed for several years to be a prerequisite for high in vivo uptake. Different radiotracers have been studied to label GRPR agonists. [68Ga]AMBA is a potent Ga-68-labeled GRPR agonist. Baum et al. studied [68Ga]AMBA in different malignancies and reported that it was tumor-specific (no significant uptake was seen in other organs) and it was well-tolerated by patients [42]. [68Ga]AMBA identified metastatic disease in one PC patient, and it was used for treatment when radiolabeled with Lu-177 ([177Lu]AMBA). However, a study, comparing the agonist [111In]AMBA to its antagonist [111In]RM1, showed the superiority of the radioantagonist regarding the high tumor uptake and tumor-to-normal tissue ratio, both in vitro and in vivo [43]. Fluorine-18-labeled bombesin agonists have also been assessed: The agonist—NOTA-8-Aoc-BBN(714)NH(2)—was studied by Dijkgraaf et al., and they demonstrated that it specifically accumulated in the GRPRexpressing PC-3 tumors [28]. Carlucci et al. developed two novel F-18-labeled BBN analogs that demonstrated high stability in GRPR expression xenograft prostate cancer models [44]. However, to our knowledge, they have not been studied in humans yet. Lane et al. synthesized a series of [64Cu]NO2A-(X)BBN(7-14) NH2 agonists for the specific targeting of GRPR on human prostate PC-3 tumor cells and tumor tissue in vitro and in vivo imaging studies. Among these agonists, the [64Cu]NO2A-(AMBA) BBN(7-14) NH2 conjugate reported the highest advantages in terms of accumulation and retention in tumor tissue and clearance via the renal urinary excretion pathway. High-quality, high-contrast micro PET/ CT images were also obtained in mice bearing PC-3 xenograft tumors [45]. Other agonists have been studied with reported high in vivo stability of the corresponding Cu64 complexes [46, 47]. Several authors have evaluated Tc99m-labeled agents [48, 49]. Overall, Tc-99m-labeled bombesin agonists had good specific tumor localization, but all the studies were performed in a small cohort of patients and they were not confirmed in larger cohorts.

Baratto L. et al.: Prostate Cancer Theranostics Targeting Peptide Receptors

The AMBA peptide was also labeled with Lu-177 ([177Lu]AMBA) [49, 50]. Thomas et al. investigated the distribution of GRPRs in human neoplastic and nonneoplastic tissues by in vitro receptor autoradiography using [177Lu]AMBA [51]. Among 40 different types of nonneoplastic tissues tested, 7 of them showed limited but specific binding of [177Lu]AMBA. Within the tumor specimens, 14 of 17 primary prostate cancers and 6 of 13 primary breast cancers expressed binding sites for [177Lu]AMBA and no differences were found in binding site expression between primary and secondary cancer tissues. Maddalena et al. also showed the therapeutic potential of [177Lu]AMBA in several prostate cancer models with different GRPR expression levels, such as PC3, LnCaP, and DU145 [39]. Overall, GRPR agonists showed good performance, but because of the undesirable effects in the gastrointestinal system after agonist-induced GRPR activation (release of gastrointestinal peptide hormones, stimulation of exocrine gland secretion, contraction of smooth musculature) [50], their use was not developed further despite their ability to internalize in cancer cells. This led to an increased interest toward their counterparts, the GRPR antagonists.

GRPR Antagonists The interest in a second-generation of GRPR radiotracers, based on GRPR antagonists, increased after discovering that antagonists of somatostatin receptors were able to recognize more binding sites than agonists and had an even better uptake and retention in tumor cells in vivo compared to their corresponding radiolabeled agonist [51, 52]. GRPR antagonists have pharmacokinetics more favorable than their agonist counterparts. While GRPR antagonists do not activate the receptor upon binding, they can successfully target and be sufficiently retained in GRPR-expressing cancer lesions while rapidly clearing from physiologic organs in both animal models and humans. Several GRPR peptides have been studied. A study by Mansi et al. [43] synthesized a new statine-based GRPR antagonist, RM1 (DOTA-Gly-aminobenzoic acid-D-PheGln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2), and compared it with its agonist counterpart [111In]AMBA. [111In]RM1 showed higher tumor uptake and higher tumor-to-normal tissue ratio than its agonist in PC-3 tumor-bearing mice. When RM1 was labeled with Ga-68, it demonstrated similar pharmacokinetics to [111In]RM1, providing a viable candidate for clinical GRPR-PET/CT studies. In 2011, the same group developed another molecule [53], RM2 (DOTA-4-amino-1-carboxymethyl-piperidine-DPhe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2), formerly also known as BAY86-7548. RM2 was labeled with In-111 and Ga-68. They were tested with in vitro PC-3 cells. Both radiotracers showed high and specific uptake in a tumor. Moderate uptake was also seen in abdominal organs

(particularly pancreas); however, the uptake in the tumor remained high with time, whereas there was a fast washout of the tracer from the other organs. Gourni et al. [54] developed a new peptide-chelator conjugate, MJ9 (H-4-amino-1-carboxymethhyl-piperidineD-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2), which was radiolabeled with Ga-68 and Cu-64 using two different chelators, i.e., NOTA (NOTA-MJ9) and NODAGA (NODAGA-MJ9). Both radiotracers were tested in vivo in PC-3 tumor xenografts by biodistribution and PET imaging studies, and both demonstrated high specificity for GRPRpositive tumors; the Cu-64 labeled conjugate showed higher tumor-to-background ratios at a later time because of the longer half-life of the metal. NeoBOMB1 is a novel DOTA-coupled GRPR antagonist with high affinity for GRPR and excellent in vivo stability. Dalm et al. explored the use of NeoBOMB1 for theranostic application by determining the biodistribution of [68Ga]NeoBOMB1 and [177Lu]NeoBOMB1 in PC-3 tumorxenografted mice. Imaging studies resulted in good visualization of the tumor with both [68Ga]NeoBOMB1 and [177Lu]NeoBOMB1 leading the authors to think that both radiotracers are promising for imaging and therapy of GRPR-expressing tumors [55]. Another group evaluated the same peptide labeled with different radiometals (Ga-67/68, In-111, and Lu-177) in GRPR-expressing cells and mouse models [56]. All the radiolabeled compounds specifically and strongly bound on the cell membrane of PC-3 cells and showed high and GRPR-specific uptake in the PC-3 xenografts. They also acquired PET/CT images with [68Ga]NeoBOMB1 in prostate cancer patients; [68Ga]NeoBOMB1 rapidly localized in pathologic lesions, achieving high-contrast imaging. Flourine-18 has also been used to label GRPR antagonists [33, 57]; overall, the compounds show high and specific accumulation in GRPR-positive PC-3 tumors. [18F]-AlNOTA-MATBBN ([ 18F]fluoropropyl-Gly-Gly-Gly-ArgAsp-Asn-D-Phe-Gln-Trp-Ala-Val-Gly-His-LeuNHCH2CH3) is a GRPR antagonist that has been tested in PC-3 tumor-bearing mice demonstrating favorable tumor uptake, tumor-to-muscle uptake ratios, and high GRPR binding specificity. Authors concluded that [18F]-AlNOTA-MATBBN might be a promising PET imaging agent for PC [58]. The same peptide was tested using Ga-68 as radiotracer [59]. They described the targeting properties of [68Ga]NOTA-MATBBN both in vitro and in vivo and pointed out that the favorable characterizations of [68Ga]NOTA-MATBBN such as the convenient synthesis, the specific GRPR targeting, and the high tumor uptake warrant its further investigation for clinical cancer imaging. Another group labeled a novel GRPR target, JMV5132 (NODA-MPAA-βAla-βAla-[H-d-Phe-Gln-Trp-Ala-Val-GlyHis-Sta-Leu-NH2]), with F-18 and Ga-68 obtaining comparable high affinity to PC-3 tumor cells [33].

Baratto L. et al.: Prostate Cancer Theranostics Targeting Peptide Receptors

Gourni et al. developed a statine-based bombesin receptor antagonist suitable for labeling with Cu-64 for imaging by PET [60]. The novel peptide, MeCOSar-PEGxbombesin, demonstrated high affinity to GRPR in PC-3 cells. The in vivo studies showed high tumor uptake and an increase in tumor-to-background ratios with time, which made the radiotracer potentially suitable for translation into the clinic.

GRPR for Staging PC Roivainen et al. reported the first-in-human study of [68Ga]RM2 (previously known as BAY 86-7548) [61]. Five healthy men were enrolled and scanned by a dynamic whole-body [68Ga]BAY 86-7548 PET/CT. They studied the metabolism, biodistribution, and pharmacokinetics of the tracer; dosimetry was also calculated. Overall, [68Ga]RM2 demonstrated to be safe and rapidly metabolized. No adverse events were registered, and the radiation exposure was acceptable. Kahkonen et al. evaluated the same molecule, [68Ga]RM2, in prostate cancer patients [62]. This prospective study enrolled 14 men, 11 of whom had been scheduled for radical prostatectomy and 3 had biochemical recurrence after surgery or hormonal therapy. Using histology as the gold standard, [68Ga]RM2 showed sensitivity, specificity, and accuracy for the detection of primary cancer of 89, 81, and 83 %, respectively. An interesting study was reported by Zhang et al. [63]. Based on the previous discovery that both GRPR and integrin αvß3 are overexpressed in neoplastic cells of human PC [24] and that the heterodimer has advantage over the corresponding monomers because of the improved binding affinity and the increased number of effective receptors [64], these investigators assessed the clinical diagnostic value of [68Ga]BBN-RGD PET/CT in PC patients in comparison with [68Ga]BBN. They enrolled 13 patients with PC, and they reported a better performance of the heterodimer in terms of detection rate ([68Ga]BBN-RGD detected more primary tumors, metastatic lymph nodes, and bone lesions than [ 68 Ga]BBN). On a semi-quantitative analysis, [68Ga]BBN-RGD showed higher uptake compared to the corresponding monomers. However, both angiogenesis and GRPR can be targets for therapies such as bevacizumab or Lu-177-labeled bombesin analogs (9), respectively, making it difficult for a treating physician to decide the use of one versus the other based on a [68Ga]BBN-RGD PET scan [65]. Copper-64 complexes have also been analyzed. [64Cu]CB-TE2A-AR06 ([64Cu]-4,11-bis(carboxymethyl)1,4,8,11-tetraazabicyclo(6.6.2)hexadecane)-PEG4-D-PheGln-Trp-Ala-Val-Gly-His-Sta-LeuNH2) was studied by PET/CT in four patients with newly diagnosed prostate cancer (T1c-T2b, Gleason 6–7) [66]. No adverse events were observed, and tumors were visualized with high contrast.

Two human studies employed BBNanalogs with Tc-99m. Ananias et al. [67] explored a BBN-based radiopharmaceutical ([99mTc]HYNIC(tricine/TPPTS)-Aca-Bombesin(7-14) [99mTc]HABBN) for the first time in humans. Eight patients with biopsy-proven PC underwent [99mTc]HABBN scintigraphy and single-photon emission computed tomography (SPECT)/CT prior to either prostatectomy or external beam radiotherapy. Immunohistochemical staining for GRPR was taken for all prostate cancer specimens. The results were not exciting: All proven PC specimens expressed GRPR, but neither planar scintigraphy nor SPECT/CT detected any PC lesions. In 2014, another BBN analog was tested for the first time in men [68]. This was a non-therapeutic phase I trial testing of [99mTc]DB4 for imaging PC. A total of eight patients with biopsy-proven PC were enrolled into the study. [99mTc]DB4 planar and SPECT/CT imaging were evaluated for increased uptake in the primary tumor and sites of metastatic disease and compared to conventional imaging (bone scan, CT, and MR imaging when available). For primary tumor, an increased uptake was seen in patients who did not receive prior therapy, while there was no uptake in the prostate gland of all patients who underwent treatment before imaging. No uptake was seen in the lymph nodes, and variable uptake was seen on bone metastases. Authors concluded that the radiopharmaceutical is unsuitable for imaging refractory PC, but it can have a role in untreated patients.

GRPR for Restaging PC Van de Wiele et al. performed the first clinical use of a BNbased radiopharmaceutical using a Tc-99m BN analog peptide. The study showed tumor uptake in four of six breast cancers and one of four androgen-resistant metastatic prostate carcinomas [48]. Since that time, few other clinical studies have been published, and further clinical evaluation of BN analog peptide is needed. A recent study compared [68Ga]RM2 with 18 [ F]fluoroethylcholine ([18F]ECH) PET/CT in patients with biochemically recurrent PC [69]. They retrospectively analyzed 16 men with biochemical relapse and negative or inconclusive [18F]ECH PET/CT. Overall, [68Ga]RM2 PET/ CT showed abnormal uptake in 10 of 16 patients (63 %): For 2 patients with inconclusive results in [18F]ECH PET/CT, [68Ga]RM2 showed additional lymph nodes in the pelvis and multiple bone lesions. However, the median PSA at the time of 1[18F]ECH PET/CT was lower than that at the time of [68Ga]RM2 PET/CT (2.4 vs 5.5 ng/ml, respectively) and further investigation in larger prospective clinical trials is needed to confirm these data. A pilot study was published by our group comparing the biodistribution of [68Ga]RM2 and [68Ga]PSMA-11 in seven patients with biochemically recurrent prostate cancer and non-contributory results on conventional imaging (bone scan, CT, and/or MRI) [70]. Patients underwent

Baratto L. et al.: Prostate Cancer Theranostics Targeting Peptide Receptors

conventional imaging, a RM2 PET/MRI, and a PSMA PET/ CT. The study highlighted the differences in the biodistribution of the two PET radiopharmaceuticals, such as different excretory routes (both renal and hepatobiliary for PSMA-11 and mainly renal for RM2), which may have implications in the detection of pelvic and abdominal lesions. The two radiopharmaceuticals showed similar, but not identical, uptake patterns of distribution in the suspected lesions, which may be due to the heterogeneous expression of PSMA and GRP in the course of disease. In patients with biochemical recurrence, [68Ga]RM2 was compared with either [ 1 1 C]acetate or [ 1 8 F] fluoromethylcholine PET/CT. Overall, using histology as the standard of reference, [68Ga]RM2 PET/CT reported a sensitivity of 70 % for the detection of metastatic lymph nodes. In two patients with biochemical relapse, [68Ga]RM2 PET/CT was in accordance with [11C]acetate PET/CT and correctly detected local recurrence in prostate bed and nodal relapse, while it failed to recognize multiple bone lesions detected by [ 18 F]fluoromethyl-choline PET/CT in a hormone-refractory PC patient [64]. Another peptide, [68Ga]SB3, has been investigated by Maina et al. [71]. They injected the radiotracer in patients with prostate (nine patients) and breast cancers (eight patients). All patients had disseminated disease and had

received previous therapies. [68Ga]SB3 PET/CT visualized lesions in about 50 % of patients (four out of eight BC patients (50 %) and five of nine PC patients (55 %)), and it elicited no adverse effects. The mean PSA level of PC patients was 64 ± 81 ng/ml (range 1.5–215 ng/ml). For four patients with a positive [68Ga]SB3 scan, PSA levels were high (≥ 10 ng/ml). One out of four patients with a negative [68Ga]SB3 scan had normal PSA levels. Our group has recently published a prospective study evaluating [68Ga]RM2 PET/MRI in 32 patients with biochemical recurrence of PC and negative conventional imaging. [68Ga]RM2 imaging and MR imaging have identified recurrent disease in 23 and 11 of these patients, respectively [72]. Examples are shown in Figs. 1 and 2. Table 1 shows a summary of GRPR analogs tested in clinical studies.

Conclusions Radiolabeled bombesin analogs are very promising candidates for imaging and therapy of prostate cancer patients. GRPR antagonists have more favorable characteristics compared to agonists: They have higher tumor/ background ratio, because of better washout, and they do not induce adverse effects. Furthermore, GRPR analogs

Fig. 1 Sixty-six-year-old man with prostate cancer, now with biochemical recurrence and PSA of 7.9 ng/ml. Focal uptake corresponding to retroperitoneal lymph nodes [72] is seen on a maximum-intensity projection [68Ga]RM2 PET image, b axial [68Ga]RM2 PET image, c T1-weighted axial MRI, and d fused PET/MRI.

Baratto L. et al.: Prostate Cancer Theranostics Targeting Peptide Receptors

Fig. 2 Sixty-eight-year-old man with prostate cancer, now with biochemical recurrence and PSA of 11.31 ng/ml. Focal uptake corresponding to the left pelvic lymph node [72] is seen on a maximum-intensity projection [68Ga]RM2 PET image, b axial [68Ga]RM2 PET image, c T1-weighted axial MRI, and d fused PET/MRI. Focal uptake corresponding to the presacral pelvic lymph node [72] is seen on e axial [68Ga]RM2 PET image, f T1-weighted axial MRI, and g fused PET/MRI.

biodistribution appears to be favorable for theranostic use, showing lower salivary gland and renal activities than other PC tracers. Many encouraging preclinical studies have been published evaluating bombesin analogs radiolabeled with different isotopes, and the premises for the introduction of these molecules into clinical practice are promising. Novel targets, resistance mechanisms, and relevant agents

are being tested in clinical trials to develop a personalized management of PC patients. In this scenario, GRPR tracers could be considered as biomarkers that possess the ability to guide diagnosis as well as treatment of PC. However, larger prospective clinical trials are needed to bolster the correlation between preclinical studies in mouse tumor models and the preliminary in vivo performance in cancer patients.

Table 1. GRPR analogs used in clinical studies GRPR analog

Radioisotopes

Patients

References

RP527 BN AMBA

Tc-99m Tc-99m Ga-68

Van de Wiele et al. [48] Scopinaro et al. [49] Baum et al. [42]

RM2 RM2 HABBN DB4 CB-TE2A-AR06 RM2

Ga-68 Ga-68 Tc-99m Tc-99m Cu-64 Ga-68

SB3 BBN-RGD NeoBOMB1 RM2 RM2

Ga-68 Ga-68 Ga-68 Ga-68 Ga-68

10 patients with metastasized PC or breast cancer 10 patients with suspected PC 10 patients with different malignancies (medullary thyroid, prostate, colon, breast, and uterine carcinomas) 5 healthy men 14 patients with primary PC, with biochemical recurrence, or in hormonal therapy 8 patients with biopsy-proven PC 8 patients with PC 4 patients with newly diagnosed PC (T1c-T2b, Gleason 6–7) 7 patients with biochemically recurrent PC and non-contributory results on conventional imaging 17 patients with disseminated breast and PC who had received previous therapies 13 patients with PC 4 patients with PC 16 patients with recurrent PC 32 patients with biochemical recurrence of PC and negative conventional imaging

Roivainen et al. [61] Kahkonen et al. [62] Ananias et al. [67] Mather et al. [68] Wieser et al. [66] Minamimoto et al. [70] Maina et al. [71] Zhang et al. [63] Nock et al. [56] Wieser et al. [69] Minamimoto et al. [72]

Baratto L. et al.: Prostate Cancer Theranostics Targeting Peptide Receptors

Compliance with Ethical Standards

17.

Conflict of Interest The authors declare that they have no conflict of interest. 18.

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