The somatostatin analogue [DOTA0,Tyr3]octreotate has a nine-fold higher affinity for the somatostatin receptor subtype 2 as compared with [DOTA0, Tyr3]octreotide. Also, labelled with the beta- and gamma-emitting radionuclide lutetium-177, this compound has been shown to have a very favourable impact on tumour regression and animal survival in a rat model. Because of these reported advantages over the analogues currently used for somatostatin receptor-mediated radiotherapy, we decided to compare [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) with [111In-DTPA0]octreotide (111In-octreotide) in six patients with somatostatin receptor-positive tumours. Plasma radioactivity after 177Lu-octreotate expressed as a percentage of the injected dose was comparable with that after 111In-octreotide. Urinary excretion of radioactivity was significantly lower than after 111In-octreotide, averaging 64% after 24 h. The uptake after 24 h, expressed as a percentage of the injected dose of 177Lu-octreotate, was comparable to that after 111In-octreotide for kidneys, spleen and liver, but was three- to fourfold higher for four of five tumours. The spleen and kidneys received the highest absorbed doses. The doses to the kidneys were reduced by a mean of 47% after co-infusion of amino acids. It is concluded that in comparison with the radionuclide-coupled somatostatin analogues that are currently available for somatostatin receptor-mediated radiotherapy, 177Lu-octreotate potentially represents an important improvement. Higher absorbed doses can be achieved to most tumours, with about equal doses to potentially dose-limiting organs; furthermore, the lower tissue penetration range of 177Lu as compared with 90Y may be especially important for small tumours.

177 Lu, it has proved very successful in achieving tumour regression in animal models. The effects of 177 Lu-octreotate therapy were studied in 35 patients with neuroendocrine gastro-entero-pancreatic (GEP) tumours who underwent follow-up for 3-6 months after receiving their final dose. Patients were treated with doses of 100, 150 or 200 mCi 177 Lu-octreotate, to a final cumulative dose of 600-800 mCi, with treatment intervals of 6-9 weeks. Nausea and vomiting within the first 24 h after administration were present in 30% and 14% of the administrations, respectively. WHO toxicity grade 3 anaemia, leucocytopenia and thrombocytopenia occurred after 0%, 1% and 1% of the administrations, respectively. Serum creatinine and creatinine clearance did not change significantly. The effects of the therapy on tumour size were evaluable in 34 patients. Three months after the final administration, complete remission was found in one patient (3%), partial remission in 12 (35%), stable disease in 14 (41%) and progressive disease in seven (21%), including three patients who died during the treatment period. Tumour response was positively correlated with a high uptake on the octreoscan, limited hepatic tumour mass and a high Karnofsky Performance Score. Because of the limited efficacy of alternative therapies, many physicians currently adopt an expectant attitude when dealing with patients with metastatic GEP tumours. However, in view of the high success rate of therapy with 177 Lu-octreotate and the absence of serious side-effects, we advocate its use in patients with GEP tumours without waiting for tumour progression.

Protein aggregation is the hallmark of neurodegeneration but the molecular mechanisms underlying late-onset Alzheimer’s disease (AD) remain unclear. Here we integrated transcriptomic, proteomic and epigenomic analyses of post-mortem human brains to identify molecular pathways involved in AD. RNA-seq analysis revealed upregulation of transcription- and chromatin-related genes, including the histone acetyltransferases for H3K27ac and H3K9ac. An unbiased proteomic screening singled out H3K27ac and H3K9ac as main enrichments specific to AD. In turn, epigenomic profiling revealed gains of H3K27ac and H3K9ac linked to transcription, chromatin, and disease pathways in AD. Increasing genome-wide H3K27ac and H3K9ac in a fly model of AD exacerbated amyloid-β42-driven neurodegeneration. Together, these findings suggest that AD involves a reconfiguration of the epigenome, where H3K27ac and H3K9ac impact disease pathways by dysregulating transcription- and chromatin-gene feedback loops. The identification of this process highlights potential epigenetic strategies for early-stage disease treatment.

The gastrin-releasing peptide receptor (GRPr) is overexpressed on various human tumors. The goal of our study was the synthesis of new 18F-labeled bombesin analogues for the PET imaging of GRPr expression in prostate tumor using a silicon-based one-step n. c. a. radiolabeling method. The silicon-containing building blocks were efficiently coupled to the N-terminus of the peptides via solid-phase synthesis. Radiolabeling of the obtained peptide precursors proceeded smoothly under acidic conditions (34-85% conversion). Using the di-tert-butyl silyl building block as labeling moiety, products containing a hydrolytically stable 18F-label were obtained. In in vitro receptor binding experiments 2-(4-(di-tert-butylfluorosilyl)phenyl)acetyl-Arg-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH 2 ( 4b, IC50 = 22.9 nM) displayed a 12-fold higher binding affinity than 2-(4-(di-tert-butylfluorosilyl)phenyl)acetyl-Arg-Ava-Gln-Trp-Ala-Val-Gly-His(3Me)-Sta-Leu-NH2 ( 3b, IC50 = 276.6 nM), and 4b was therefore chosen for further evaluation. In vitro and ex vivo metabolite studies of [18F]4b showed no significant degradation. In biodistribution experiments, tumor uptake of [18F]4b was low and unspecific, whereas the GRPr-rich pancreas revealed a high and specific accumulation of the radiotracer. This study demonstrates the applicability of our silicon-based one-step n. c. a. radiolabeling method for the synthesis of new 18F-labeled bombesin derivatives. This innovative approach represents a general, straightforward access to radiolabeled peptides as PET imaging probes.

Radio‐controlled landing of F: The facile 18F labeling of biomolecules has been achieved under mild conditions by using a unique silicon‐based one‐step approach (see scheme). A di‐tert‐butylsilyl derivative with an aryl linker was attached to a tetrapeptide. The assembly shows a hydrolytic stability that appears to be within the range required for in vivo positron emission tomography (PET) imaging applications.

Advances in precision molecular imaging promise to transform our ability to detect, diagnose and treat disease. Here, we describe the engineering and validation of a new cystine knot peptide (knottin) that selectively recognizes human integrin αvβ6 with single-digit nanomolar affinity. We solve its 3D structure by NMR and x-ray crystallography and validate leads with 3 different radiolabels in pre-clinical models of cancer. We evaluate the lead tracer’s safety, biodistribution and pharmacokinetics in healthy human volunteers, and show its ability to detect multiple cancers (pancreatic, cervical and lung) in patients at two study locations. Additionally, we demonstrate that the knottin PET tracers can also detect fibrotic lung disease in idiopathic pulmonary fibrosis patients. Our results indicate that these cystine knot PET tracers may have potential utility in multiple disease states that are associated with upregulation of integrin αvβ6.

No abstract

Previous studies have shown that modification of the somatostatin analogue octreotide (OC), by substitution of tyrosine for phenylalanine at position 3 and of a C-terminal carboxylic acid for an alcohol, to give Tyr3-octreotate (Y3-TATE) improved uptake of the peptide in somatostatin receptor-positive tissues. To determine which substitution best accounts for increased target tissue uptake, the peptides containing single modifications, Tyr3-octreotide (Y3-OC) and octreotate (TATE), were synthesized. These peptides were conjugated to the macrocyclic chelating agent 1,4,8, 11-tetraazacyclotetradecane-N,N',N",N"'-tetraacetic acid (TETA) and radiolabeled with 64Cu(II). The in vitro receptor binding, in vitro tumor cell uptake, and in vivo distribution properties of 64Cu-labeled TETA-Y3-OC and TETA-TATE were compared to those of [64Cu]TETA-OC and [64Cu]TETA-Y3-TATE. Cu-TETA-TATE (IC50 = 0.297 +/- 0.0055 nM) and Cu-TETA-Y3-TATE (IC50 = 0.308 +/- 0.0375 nM) displayed significantly higher binding affinity to somatostatin receptors on CA20948 rat pancreatic tumor membranes than Cu-TETA-Y3-OC (IC50 = 0.397 +/- 0.0206 nM) and Cu-TETA-OC (IC50 = 0. 498 +/- 0.039 nM). Similarly, the uptakes of [64Cu]TETA-Y3-TATE (60. 75 +/- 1.21%) and [64Cu]TETA-TATE (55.62 +/- 0.16%) into AR42J rat pancreatic tumor cells over a 2-h time period were higher than those of [64Cu]TETA-Y3-OC (47.20 +/- 1.20%) and [64Cu]TETA-OC (34.07 +/- 2. 24%). The in vitro results suggest that the C-terminal carboxylate may contribute more to enhanced receptor binding and tumor cell uptake than the substitution at the 3-position. Biodistributions in CA20948 tumor-bearing rats showed receptor-mediated uptake of the 64Cu-labeled peptides in somatostatin-rich tissues, including the pituitary, adrenals, pancreas, and tumor. The structure-activity relationships of the four 64Cu-labeled peptides did not show consistent trends in all target tissues, but [64Cu]TETA-Y3-TATE exhibited tumor uptake 1.75-3.5 times higher than the other derivatives at 4 h postinjection. The greater tumor retention of [64Cu]TETA-Y3-TATE justifies the selection of this agent for future PET imaging and targeted radiotherapy studies.