Aviral Singh

What can gallium-68 PET add to receptor and molecular imaging?

In the last decade there has been a significant increase in the development of radiolabelled peptides for diagnostic applications, especially due to simplified methods of purification. Peptides have fast clearance, rapid tissue penetration, and low antigenicity and can therefore be produced easily and inexpensively. In addition, if the diagnostic scan is positive, the peptides can be labelled with therapeutic radionuclides (yttrium-90, lutetium-177) and used for therapy [1]. Most efforts at labelling peptides have targeted somatostatin and its receptors. Somatostatin is a regulatory peptide widely distributed in the human body. Its action is mediated by membrane-bound receptors (SSTR) that are present in normal human tissues, such as thyroid, brain, gastrointestinal tract (GIT), pancreas, spleen and kidney [2]. They are also abundant in a variety of human tumours, notably neuroendocrine tumours (NET) [3] of which carcinoid tumour and phaeochromocytoma are encountered most in clinical practice. SSTR are also expressed, with variable abundance, in renal cell carcinoma, small cell lung cancer, breast cancer, prostate cancer and malignant lymphoma [4]. Somatostatin itself has a short half-life and is rapidly degraded by enzymes; therefore analogues have been developed which mimic its effects but are resistant to enzyme degradation. There are 5 somatostatin receptor subtypes but only subtypes 2 (SSTR2) and 5 (SSTR5) and to a lesser extent receptor subtype 3 (SSTR3) have a high affinity for commercially available synthetic analogues and even these differ in their affinity for the various receptor subtypes [5].

PSMA-Based Radioligand Therapy for Metastatic Castration-Resistant Prostate Cancer: The Bad Berka Experience Since 2013

A potential milestone in personalized nuclear medicine is theranostics of metastatic castration-resistant prostate cancer (mCRPC) based on molecular imaging using PET/CT with 68Ga-labeled prostate-specific membrane antigen (PSMA) ligands and molecular radiotherapy using PSMA-targeted radioligand therapy (PRLT) with 177Lu-PSMA ligands. 68Ga-PSMA PET/CT enables accurate detection of mCRPC lesions with high diagnostic sensitivity and specificity and provides quantitative and reproducible data that can be used to select patients for PRLT and therapeutic monitoring. Our comprehensive experience over the last 3 years using different radioligands indicates that PRLT is highly effective for the treatment of mCRPC, even in advanced cases, and potentially lends a significant benefit to overall and progression-free survival. Additionally, significant improvement in clinical symptoms and excellent palliation of pain can be achieved.

Theranostic Perspectives in Prostate Cancer with the Gastrin-Releasing Peptide Receptor Antagonist NeoBOMB1: Preclinical and First Clinical Results

We recently introduced the potent gastrin-releasing peptide receptor (GRPR) antagonist 68Ga-SB3 (68Ga-DOTA-p-aminomethylaniline-diglycolic acid-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt), showing excellent tumor localizing efficacy in animal models and in patients. By replacement of the C-terminal Leu13-Met14-NH2 dipeptide of SB3 by Sta13-Leu14-NH2, the novel GRPR antagonist NeoBOMB1 was generated and labeled with different radiometals for theranostic use. We herein report on the biologic profile of resulting 67/68Ga-, 111In-, and 177Lu-NeoBOMB1 radioligands in GRPR-expressing cells and mouse models. The first evidence of prostate cancer lesion visualization in men using 68Ga-NeoBOMB1 and PET/CT is also presented. Methods: NeoBOMB1 was radiolabeled with 67/68Ga, 111In, and 177Lu according to published protocols. The respective metalated species natGa-, natIn-, and natLu-NeoBOMB1 were also synthesized and used in competition binding experiments against [125I-Tyr4]BBN in GRPR-positive PC-3 cell membranes. Internalization of 67Ga-, 111In-, and 177Lu-NeoBOMB1 radioligands was studied in PC-3 cells at 37°C, and their metabolic stability in peripheral mouse blood was determined by high-performance liquid chromatography analysis of blood samples. Biodistribution was performed by injecting a 67Ga-, 111In-, or 177Lu-NeoBOMB1 bolus (74, 74, or 370 kBq, respectively, 100 μL, 10 pmol total peptide ± 40 nmol Tyr4-BBN: for in vivo GRPR blockade) in severe combined immunodeficiency mice bearing PC-3 xenografts. PET/CT images with 68Ga-NeoBOMB1 were acquired in prostate cancer patients. Results: NeoBOMB1 and natGa-, natIn-, and natLu-NeoBOMB1 bound to GRPR with high affinity (half maximal inhibitory concentration, 1–2 nM). 67Ga-, 111In-, and 177Lu-NeoBOMB1 specifically and strongly bound on the cell membrane of PC-3 cells displaying low internalization, as expected for receptor antagonists. They showed excellent metabolic stability in peripheral mouse blood (>95% intact at 5 min after injection). After injection in mice, all 3 (67Ga-, 111In-, and 177Lu-NeoBOMB1) showed comparably high and GRPR-specific uptake in the PC-3 xenografts (e.g., 30.6 ± 3.9, 28.6 ± 6.0, and >35 percentage injected dose per gram at 4 h after injection, respectively), clearing from background predominantly via the kidneys. During a translational study in prostate cancer patients, 68Ga-NeoBOMB1 rapidly localized in pathologic lesions, achieving high-contrast imaging. Conclusion: The GRPR antagonist radioligands 67Ga-, 111In-, and 177Lu-NeoBOMB1, independent of the radiometal applied, have shown comparable behavior in prostate cancer models, in favor of future theranostic use in GRPR-positive cancer patients. Such translational prospects were further supported by the successful visualization of prostate cancer lesions in men using 68Ga-NeoBOMB1 and PET/CT.

Theranostic Prospects of Gastrin-Releasing Peptide Receptor–Radioantagonists in Oncology

Gastrin-releasing peptide receptors (GRPRs) represent attractive targets for cancer diagnosis and therapy owing to their overexpression in widespread human tumors. Bombesin (BBN) analogues coupled to suitable chelators for stable radiometal binding have been proposed for diagnostic imaging and radionuclide therapy (theranostics) of GRPR-positive tumors. Recently, interest has shifted from BBN-like receptor agonists to GRPR-radioantagonists, because radioantagonists do not induce adverse effects after injection to patients and display superior pharmacokinetic in vivo profiles. Thus, they seem more advantageous for clinical use compared to agonists. Newer developments highlighting the theranostic potential of GRPR-radioantagonists in cancer patient management are presented herein.

Imaging of Prostate Cancer Using 64Cu-Labeled Prostate-Specific Membrane Antigen Ligand

Prostate cancer is the most common noncutaneous cancer among men, rendering the diagnosis and staging of significant medical and public interest. One of the most interesting developments in the application of nuclear oncology has been the development of novel diagnostic agents that are able to facilitate targeted therapies using the concept of theranostics. This review summarizes the current and emerging molecular imaging techniques for the investigation of patients with prostate cancer with emphasis on the potential of 64Cu-PSMA PET/CT in staging, restaging, and the application of theranostics.

Investigating the Effect of Ligand Amount and Injected Therapeutic Activity: A Simulation Study for 177Lu-Labeled PSMA-Targeting Peptides.

In molecular radiotherapy with 177Lu-labeled prostate specific membrane antigen (PSMA) peptides, kidney and/or salivary glands doses limit the activity which can be administered. The aim of this work was to investigate the effect of the ligand amount and injected activity on the tumor-to-normal tissue biologically effective dose (BED) ratio for 177Lu-labeled PSMA peptides. For this retrospective study, a recently developed physiologically based pharmacokinetic model was adapted for PSMA targeting peptides. General physiological parameters were taken from the literature. Individual parameters were fitted to planar gamma camera measurements (177Lu-PSMA I&T) of five patients with metastasizing prostate cancer. Based on the estimated parameters, the pharmacokinetics of tumor, salivary glands, kidneys, total body and red marrow was simulated and time-integrated activity coefficients were calculated for different peptide amounts. Based on these simulations, the absorbed doses and BEDs for normal tissue and tumor were calculated for all activities leading to a maximal tolerable kidney BED of 10 Gy2.5/cycle, a maximal salivary gland absorbed dose of 7.5 Gy/cycle and a maximal red marrow BED of 0.25 Gy15/cycle. The fits yielded coefficients of determination > 0.85, acceptable relative standard errors and low parameter correlations. All estimated parameters were in a physiologically reasonable range. The amounts (for 25−29 nmol) and pertaining activities leading to a maximal tumor dose, considering the defined maximal tolerable doses to organs of risk, were calculated to be 272±253 nmol (452±420 μg) and 7.3±5.1 GBq. Using the actually injected amount (235±155 μg) and the same maximal tolerable doses, the potential improvement for the tumor BED was 1–3 fold. The results suggest that currently given amounts for therapy are in the appropriate order of magnitude for many lesions. However, for lesions with high binding site density or lower perfusion, optimizing the peptide amount and activity might improve the tumor-to-kidney and tumor-to-salivary glands BED ratio considerably.

Clinical significance of myocardial perfusion abnormalities in patients with varying degree of coronary artery stenosis.

Objectives(1) To identify myocardial perfusion abnormalities in a cohort of patients having coronary artery disease (CAD) risk factors, with either suspected or clinical evidence of ischaemic heart disease (IHD), and with varying degree of coronary artery stenosis. (2) To evaluate the clinical significance of the extent and severity of perfusion abnormalities assessed by myocardial perfusion scintigraphy (MPS) in relation to the anatomical location of coronary stenosis demonstrated by five-vessel selective coronary angiography (SCA). MethodsOne hundred and thirty-eight patients (106 male, 32 female) with suspected or clinical evidence of IHD underwent diagnostic evaluation at the Central Hospital of Nicosia, between November 2002 and August 2003. The diagnostic work-up included clinical examination, exercise tolerance test, SCA and myocardial perfusion scintigraphy (MPS) using either 201Tl chloride or 99mTc-tetrofosmin. ResultsBased on the results of SCA, patients were divided into five groups on the basis of stenosis as cross-sectional area of coronary artery lumen and its haemodynamic significance, ranging from group 1=less than 50% coronary stenosis to group 5=100% stenosis (occlusion). Nine of 11 (40.9%) patients with angiographically normal coronary arteries (group 1) had moderate inducible reversible ischaemia on MPS and 9/47 (19.1%) patients with insignificant coronary stenosis (less than 75% stenosis=group 2) had fixed perfusion defects, compatible with previous myocardial infarction. The extent of perfusion abnormalities in post-stress MPS patients from group 2 was not found to be statistically significant (P>0.05) when compared to patients belonging to groups 3, 4 and 5. However, the extent of perfusion abnormalities between patients from group 2, when compared to groups 3, 4 and 5 demonstrated significant statistical difference (P<0.05) on post-rest MPS studies. Furthermore, there was no significant statistical correlation between anatomical location of coronary stenosis and severity of perfusion abnormalities in the corresponding myocardial segments. ConclusionPatients with CAD risk factors, and coronary arteries with insignificant stenosis on angiography, may demonstrate inducible reversible myocardial ischaemia. This is suggestive of coronary endothelial dysfunction. Patients with insignificant coronary artery stenosis and no previous history of adverse coronary events may demonstrate features of previous myocardial infarction on MPS. The severity of perfusion defects demonstrated by MPS may be independent of the anatomical location of coronary artery stenosis.

177Lu-3BP-227 for Neurotensin Receptor 1–Targeted Therapy of Metastatic Pancreatic Adenocarcinoma: First Clinical Results

Neurotensin receptor 1 (NTR1) is overexpressed in ductal pancreatic adenocarcinoma, which is still one of the deadliest cancers, with a very poor prognosis. Eligible patients were offered salvage radiopharmaceutical therapy with the novel NTR1 antagonist 177Lu-3BP-227. Methods: Six patients with confirmed ductal pancreatic adenocarcinoma who had exhausted all other treatment options received 177Lu-3BP-227 for evaluation of NTR1 expression in vivo. Three patients received treatment activities of 5.1–7.5 GBq. Results: Administration of 177Lu-3BP-227 was well tolerated by all patients. The kidneys were identified as the dose-limiting organ. The most severe adverse event was reversible grade 2 anemia. One patient achieved a partial response and experienced significant improvement of symptoms and quality of life. This patient survived 13 mo from diagnosis and 11 mo from the start of 177Lu-3BP-227 therapy. Conclusion: This initial report provides clinical evidence of the feasibility of treatment of ductal pancreatic adenocarcinoma using 177Lu-3BP-227.

Results and adverse events of personalized peptide receptor radionuclide therapy with 90 Yttrium and 177 Lutetium in 1048 patients with neuroendocrine neoplasms

Introduction Peptide receptor radionuclide therapy (PRRT) of patients with somatostatin receptor expressing neuroendocrine neoplasms has shown promising results in clinical trials and a recently published phase III study. Methods In our center, 2294 patients were screened between 2004 and 2014 by 68Ga somatostatin receptor (SSTR) PET/CT. Intention to treat analysis included 1048 patients, who received at least one cycle of 90Yttrium or 177Lutetium-based PRRT. Progression free survival was determined by 68Ga SSTR-PET/CT and EORTC response criteria. Adverse events were determined by CTCAE criteria. Results Overall survival (95% confidence interval) of all patients was 51 months (47.0-54.9) and differed significantly according to radionuclide, grading, previous therapies, primary site and functionality. Progression free survival (based on PET/CT) of all patients was 19 months (16.9-21), which was significantly influenced by radionuclide, grading, and origin of neuroendocrine neoplasm. Progression free survival after initial progression and first and second resumption of PRRT after therapy-free intervals of more than 6 months were 11 months (9.4-12.5) and 8 months (6.4-9.5), respectively. Myelodysplastic syndrome or leukemia developed in 22 patients (2.1%) and 5 patients required hemodialysis after treatment, other adverse events were rare. Conclusion PRRT is effective and overall survival is favorable in patients with neuroendocrine neoplasms depending on the radionuclide used for therapy, grading and origin of the neuroendocrine neoplasm which is not exactly mirrored in progression free survival as determined by highly sensitive 68Ga somatostatin receptor PET/CT using EORTC criteria for determining response to therapy.

Theranostics of prostate cancer: from molecular imaging to precision molecular radiotherapy targeting the prostate specific membrane antigen

Alterations at the molecular level are a hallmark of cancer. Prostate cancer is associated with the overexpression of prostate-specific membrane antigen (PSMA) in a majority of cases, predominantly in advanced tumors, increasing with the grade or Gleasons score. PSMA can be selectively targeted using radiolabeled PSMA ligands. These small molecules binding the PSMA can be radiolabeled with γ-emitters like 99mTc and 111In or positron emitters like 68Ga and 18F for diagnosis as well as with their theranostic pairs such as 177Lu (β-emitter) or 225Ac (α-emitter) for therapy. This review summarizes the theranostic role of PSMA ligands for molecular imaging and targeted molecular radiotherapy, moving towards precision oncology.