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The neuropeptide-Y (NPY) family acts through four G protein-coupled receptor subtypes in humans, namely, Y 1 , Y 2 , Y 4 , and Y 5 . A growing body of evidence suggest the involvement of the NPY system in several cancers, notably the Y 5 subtype, thus acting as a relevant target for the development of radiopharmaceuticals for imaging or targeted radionuclide therapy (TRT). Here, the [cPP(1-7),NPY(19-23),Ala 31 ,Aib 32 ,Gln 34 ]hPP scaffold, further referred to as sY 5 ago, was modified with a DOTA chelator and radiolabeled with 68 Ga and 111 In and investigated in vitro and in vivo using the MCF-7 model. For in vivo studies, MCF-7 cells were orthotopically implanted in female nude mice and imaging with small animal positron emission tomography/computed tomography (μPET/CT) was performed. At the end of imaging, the mice were sacrificed. A scrambled version of sY 5 ago, which was also modified with a DOTA chelator, served as a negative control (DOTA-[Nle]sY 5 ago&#95;scrambled). sY 5 ago and DOTA-sY 5 ago showed subnanomolar affinity toward the Y 5 (0.9 ± 0.1 and 0.8 ± 0.1 nM, respectively) and a single binding site at the Y 5 was identified. [ 68 Ga]Ga-DOTA-sY 5 ago and [ 111 In]In-DOTA-sY 5 ago were hydrophilic and showed high specific internalization (1.61 ± 0.75%/10 6 cells at 1 h) and moderate efflux (55% of total binding externalized at 45 min). On μPET/CT images, most of the signal was depicted in the kidneys and the liver. MCF-7 tumors were clearly visualized. On biodistribution studies, [ 68 Ga]Ga-DOTA-sY 5 ago was eliminated by the kidneys (∼60 %ID/g). The kidney uptake is Y 5 -mediated. A specific uptake was also noted in the liver (5.09 ± 1.15 %ID/g vs 1.13 ± 0.21 %ID/g for [ 68 Ga]Ga-DOTA-[Nle]sY 5 ago&#95;scrambled, p < 0.05), the lungs (1.03 ± 0.34 %ID/g vs 0.20 %ID/g, p < 0.05), and the spleen (0.85 ± 0.09%ID/g vs 0.16 ± 0.16%ID/g, p < 0.05). In MCF-7 tumors, [ 68 Ga]Ga-DOTA-sY 5 ago showed 12-fold higher uptake than [ 68 Ga]Ga-DOTA-[Nle]sY 5 ago&#95;scrambled (3.43 ± 2.32 vs 0.27 ± 0.15 %ID/g, respectively, p = 0.0008) at 1 h post-injection. Finally, a proof-of-principle tissular micro-imaging study on a human primary cancer sample showed weak binding of [ 111 In]In-DOTA-sY 5 ago in prostatic intra-neoplasia and high binding in the ISUP1 lesion while normal prostate was free of signal.

The imaging of Prostate-Specific Membrane Antigen (PSMA) is now widely used at the initial staging of prostate cancers in patients with a high metastatic risk. However, its ability to detect low-grade tumor lesions is not optimal., Methods: First, we prospectively performed neurotensin receptor-1 (NTS 1 ) IHC in a series of patients receiving both [ 68 Ga]Ga-PSMA-617 and [ 68 Ga]Ga-RM2 before prostatectomy. In this series, PSMA and GRP-R IHC were also available (n = 16). Next, we aimed at confirming the PSMA/GRP-R/NTS 1 expression profile by retrospective autoradiography (n = 46) using a specific radiopharmaceuticals study and also aimed to decipher the expression of less-investigated targets such as NTS 2 , SST 2 and CXCR4., Results: In the IHC study, all samples with negative PSMA staining (two patients with ISUP 2 and one with ISUP 3) were strongly positive for NTS 1 staining. No samples were negative for all three stains-for PSMA, GRP-R or NTS 1 . In the autoradiography study, binding of [ 111 In]In-PSMA-617 was high in all ISUP groups. However, some samples did not bind or bound weakly to [ 111 In]In-PSMA-617 (9%). In these cases, binding of [ 111 n]In-JMV 6659 and [ 111 In]In-JMV 7488 towards NTS 1 and NTS 2 was high., Conclusions: Targeting PSMA and NTS 1 /NTS 2 could allow for the detection of all intraprostatic lesions.

Considering the wide range of therapeutic options for localized prostate cancer (e.g., active surveillance, radiation-beam therapy, focal therapy, and radical prostatectomy), accurate assessment of the aggressiveness and localization of primary prostate cancer lesions is essential for treatment decision making. National Comprehensive Cancer Network guidelines recognize prostate-specific membrane antigen (PSMA) PET/CT for use in initial staging of high-risk primary prostate cancer. The gastrin-releasing peptide receptor (GRP-R) is a neuropeptide receptor overexpressed by low-risk prostate cancer cells. We aimed to perform the first (to our knowledge) prospective head-to-head comparison of PSMA- and GRP-R-targeted imaging at initial staging to understand how PSMA PET and GRP-R PET can be used or combined in clinical practice. Methods: This was a prospective, single-center, diagnostic cross-sectional imaging study using anonymized, masked, and independent interpretations of paired PET/CT studies in 22 patients with 68 Ga-PSMA-617 (a radiolabeled PSMA inhibitor) and 68 Ga-RM2 ( 68 Ga-DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, a radiolabeled GRP-R antagonist). We enrolled patients with newly diagnosed, biopsy-proven prostate cancer. None had received neoadjuvant hormone therapy or chemotherapy, and all underwent extended pelvic lymph node dissection. Histologic findings served as a reference. Results: On a lesion-based analysis (including lesions < 0.1 cm 3 ), 68 Ga-PSMA-617 PET/CT detected 74.3% (26/35) of all tumor lesions and 68 Ga-RM2 PET/CT detected 78.1% (25/32; 1 patient could not be offered 68 Ga-RM2 PET/CT). Paired examinations showed positive uptake of the 2 tracers in 21 of 32 lesions (65.6%), negative uptake in 5 of 32 lesions (15.6%), and discordant uptake in 6 of 32 lesions (18.8%). Uptake of 68 Ga-PSMA-617 was higher when the International Society of Urological Pathology (ISUP) score was at least 4 versus at least 1 ( P < 0.0001) or 2 ( P  = 0.0002). There were no significant differences in uptake between ISUP scores for 68 Ga-RM2. Median 68 Ga-RM2 SUV max was significantly higher than median 68 Ga-PSMA-617 SUV max in the ISUP-2 subgroup ( P  = 0.01). Conclusion: 68 Ga-RM2 PET/CT has a higher detection rate for low-ISUP tumors. Combining PSMA PET and GRP-R PET allows for better classification of intraprostatic lesions.68 Ga-RM2 PET/CT has a higher detection rate for low-ISUP tumors. Combining PSMA PET and GRP-R PET allows for better classification of intraprostatic lesions., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Inflammatory vascular disease of the arteries, such as inflamed atheromatous plaques or arteritis, may cause aneurysms or ischemic strokes. In this context, using positron emission tomography (PET) to image inflammation may help select patients who would benefit from appropriate therapeutic interventions. This study sought to assess the usefulness of the 18 kDa translocator protein (TSPO) tracers [ 11 C]-PBR28 and [ 18 F]-PBR06 for imaging inflammatory vascular disease in vitro and in vivo. Immunohistochemistry for macrophage infiltration as well as autoradiography with [ 18 F]-PBR06 were performed on eight paraffin-embedded, formalin-fixed atherosclerosis plaques prospectively collected after carotid endarterectomy of eight patients affected by ischemic stroke. Six different patients, one of whom was also included in the in vitro study, underwent PET imaging. Two patients with carotid stenosis associated with ischemic stroke were imaged with [ 18 F]-PBR06 PET/CT, and four other patients (three with large vessel vasculitis and one with bilateral carotid stenosis but without stroke) were imaged with [ 11 C]-PBR28., Results: All in vitro sections showed specific binding of [ 18 F]-PBR06, which co-localized with immunohistochemistry markers for inflammation. However, in vivo TSPO imaging with either [ 11 C]-PBR28 or [ 18 F]-PBR06 was negative in all participants., Conclusion: Despite good uptake on surgical samples in vitro, [ 11 C]-PBR28 and [ 18 F]-PBR06 are not viable clinical tools for imaging inflammatory vascular disease., Trial Registration: NCT02513589, registered 31 July 2015 and NCT00547976, registered 23 October 2007. https://clinicaltrials.gov .

Several independent studies have demonstrated the overexpression of NTS 1 in various malignancies, which make this receptor of interest for imaging and therapy. To date, radiolabeled neurotensin analogues suffer from low plasmatic stability and thus insufficient availability for high uptake in tumors. We report the development of 68 Ga-radiolabeled neurotensin analogues with improved radiopharmaceutical properties through the introduction of the silicon-containing amino acid trimethylsilylalanine (TMSAla). Among the series of novel radiolabeled neurotensin analogues, [ 68 Ga] Ga- JMV6659 exhibits high hydrophilicity (log D 7.4 = -3.41 ± 0.14), affinity in the low nanomolar range toward NTS 1 ( K d = 6.29 ± 1.37 nM), good selectivity ( K d NTS 1 / K d NTS 2 = 35.9), and high NTS 1 -mediated internalization. It has lower efflux and prolonged plasmatic half-life in human plasma as compared to the reference compound ([ 68 Ga]Ga-JMV6661 bearing the minimum active fragment of neurotensin and the same linker and chelate as other analogues). In nude mice bearing HT-29 xenograft, [ 68 Ga]Ga-JMV6659 uptake reached 7.8 ± 0.54 %ID/g 2 h post injection. Uptake was decreased to 1.38 ± 0.71 %ID/g with injection of excess of non-radioactive neurotensin. Radiation dose as extrapolated to human was estimated as 2.35 ± 0.6 mSv for a standard injected activity of 100MBq. [ 68 Ga]Ga-JMV6659 was identified as a promising lead compound suitable for PET imaging of NTS 1 -expressing tumors.

Ga-labeled prostate-specific membrane antigen inhibitors and Ga-labeled gastrin-releasing peptide receptor antagonists showed interesting results for staging biochemically recurrent prostate cancer. In this case, Ga-prostate-specific membrane antigen-617 PET/CT, Ga-RM2 PET/CT, and F-choline PET/CT were performed in a patient (66-year-old man, prostate-specific antigen = 6.7 ng/mL) with biopsy-proven Gleason 9 (5 + 4) prostate cancer, candidate for radical prostatectomy and lymph node dissection.

Purpose: Prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRP-R) are expressed in prostate cancer and can be targeted with radiolabeled inhibitors and antagonists. Their performances for the initial characterization of prostatic tumors have been barely evaluated but never compared. We aimed to gather comparative preclinical data of the role of PSMA and GRP-R targeting in prostate cancer., Procedures: We retrospectively studied 20 frozen prostatectomy samples with various metastatic risks of the D'Amico classification. Tissue samples were investigated by tissular microimaging using the radiolabeled PSMA inhibitor 111 In-PSMA-617 and the radiolabeled GRP-R antagonist 111 In-RM2. Bindings of the two radiopharmaceuticals were compared to histology and clinico-biological data (Gleason score, PSA values, metastatic risks)., Results: Binding of 111 In-PSMA-617 was high whatever the metastatic risk (p = 0.665), Gleason score (p = 0.555), or PSA value (p = 0.404) while 111 In-RM2 exhibited a significantly higher binding in the low metastatic risk group (p = 0.046), in the low PSA value group (p = 0.001), and in samples with Gleason 6 score (p = 0.006)., Conclusion: PSMA and GRP-R based imaging might have complementary performances for the initial characterization of prostatic tumors. Prospective clinical studies comparing the two tracers in this setting are needed.

Neurotensin and its high-affinity receptor, NTR₁, are involved in the growth of various tumors. Few data are available regarding NTR₁ expression in normal and tumoral human prostate tissue samples. NTR₁ expression was assessed using immunohistochemistry in 12 normal prostate tissues, 11 benign prostatic hyperplasia (BPH), 44 prostate cancers, and 15 related metastatic lymph nodes (one per patient, when available). NTR₁-staining was negative in normal prostate and BPH samples. NTR₁ was overexpressed in four out of 44 (9.1%) primary tumors. There was no clear association between NTR₁ overexpression and age, PSA-values, Gleason score, pT-status, nodal-status, or margin. NTR₁ was expressed at a high level of five out of 15 (33.3%) metastatic lymph nodes. NTR₁ overexpression was thus more frequent in metastatic lymph nodes than in primary tumors ( p = 0.038). In this limited series of samples, NTR₁ overexpression was observed in few primary prostate cancers. Upregulation was more frequent in related lymph nodes. The presence of this target in metastatic lymph nodes may open new perspectives for imaging and radionuclide therapy of prostate cancer. Factors driving NTR₁ expression in primary prostate cancer and in nodal and distant metastases still need to be characterized.

The Gastrin-Releasing Peptide Receptor (GRPR) is over-expressed in estrogen receptor (ER) positive breast tumors and related metastatic lymph nodes offering the opportunity of imaging and therapy of luminal tumors. 68Ga-RM2 binding and 18F-FDG binding in tumoral zones were measured and compared using tissue micro-imaging with a beta imager on 14 breast cancer samples (10 primaries and 4 associated metastatic lymph nodes). Results were then assessed against ER expression, progesterone receptor (PR) expression, HER2 over-expression or not and Ki-67 expression. GRPR immunohistochemistry (IHC) was also performed on all samples. We also retrospectively compared 68Ga-RM2 and 18F-FDG bindings to 18F-FDG SUVmax on the pre-therapeutic PET/CT examination, if available. 68Ga-RM2 binding was significantly higher in tumors expressing GRPR on IHC than in GRPR-negative tumors (P = 0.022). In ER+ tumors, binding of 68Ga-RM2 was significantly higher than 18F-FDG (P = 0.015). In tumors with low Ki-67, 68Ga-RM2 binding was also significantly increased compared to 18F-FDG (P = 0.029). Overall, the binding of 68Ga-RM2 and 18F-FDG displayed an opposite pattern in tumor samples and 68Ga-RM2 binding was significantly higher in tumors that had low 18F-FDG binding (P = 0.021). This inverse correlation was also documented in the few patients in whom a 18F-FDG PET/CT examination before surgery was available. Findings from this in vitro study suggest that GRPR targeting can be an alternative to 18F-FDG imaging in ER+ breast tumors. Moreover, because GRPR antagonists can also be labeled with lutetium-177 this opens new avenues for targeted radionuclide therapy in the subset of patients with progressive metastatic disease following conventional treatments., Competing Interests: The authors have declared that no competing interests exist.

We report an F-FDG linear uptake of the right popliteal artery in a 25-year-old man who underwent a PET/CT scan for unexplained chronic asthenia associated with fever symptoms, arthralgia, and subcutaneous nodes, in favor of vasculitis. The patient had a history of saphenous vein thrombosis. Thrombophilia screening finds a blood lupus anticoagulant. A biopsy of subcutaneous nodes finds an anatomopathologic lesion of polyarteritis nodosa. F-FDG PET can be useful in initial staging of polyarteritis nodosa for an early diagnosis of vasculitis, and thus, early treatment can prevent arterial complications such as occlusion or aneurysm.