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The revision of the sarcophagid species Lepidodexia (Orosarcophaga) ornata (Townsend, 1927) reveals its identity and a generic synonym. The male terminalia of this species was studied in detail for the first time and revealed its congeneric affinities with Oxyvinia Dodge, 1966. Consequently, the generic status of Orosarcophaga Townsend, 1927 was revalidated, including Oxyvinia Dodge, 1966 as its junior synonym, and O. ornata was corroborated as a valid species and name. Moreover, we provide an updated generic diagnosis of Orosarcophaga, a list of the eleven species of the genus with their distribution, and a detailed diagnosis of O. ornata.

This account highlights the development of theragnostic pairs of radionuclides for imaging and therapy. The current use of diagnostic positron emission tomographic imaging with agents radiolabeled with gallium-68 to guide radionuclide therapy with lutetium-177 based agents, is introduced before discussing recent advances that use the positron emitting radionuclide copper-64 for diagnostic imaging and β-emitting radionuclide copper-67 for therapy. The use of cage amine sarcophagine ligands, that have complexes of excellent thermodynamic and kinetic stability with radionuclides of copper(II), to develop new theragnostic radiopharmaceuticals to enable targeting of prostate cancers and a variety of somatostatin positive neuroendocrine tumors, is discussed. The use of in vivo pretargeted radioimmunotherapy utilizing tetrazine trans-cyclooctene click chemistry is discussed focusing on the development of a single radioligand that is able to incorporate both diagnostic and therapeutic radionuclides. Finally, the latest advances in targeted radionuclide therapy with the α-emitting actinium-225 radionuclide are discussed.

The Glucagon-like peptide 1 receptor (GLP-1R) has become an important target for imaging due to its elevated expression profile in pancreatic islets, insulinoma, and the cardiovascular system. Because native GLP-1 is degraded rapidly by dipeptidyl peptidase-IV (DPP-IV), several studies have conjugated different chelators to a more stable analog of GLP-1 (such as exendin-4) as PET or SPECT imaging agents with various advantages and disadvantages. Based on the recently developed Sarcophagin chelator, here, we describe the construction of GLP-1R targeted PET probes containing monomeric and dimeric exendin-4 subunit. The in vitro binding affinity of BarMalSar-exendin-4 and Mal2Sar-(exendin-4)2 was evaluated in INS-1 cells, which over-express GLP-1R. Mal2Sar-(exendin-4)2 demonstrated around 3 times higher binding affinity compared with BaMalSar-exendin-4. After (64)Cu labeling, microPET imaging of (64)Cu-BaMalSar-exendin-4 and (64)Cu-Mal2Sar-(exendin-4)2 were performed on subcutaneous INS-1 tumors, which were clearly visualized with both probes. The tumor uptake of (64)Cu-Mal2Sar-(exendin-4)2 was significantly higher than that of (64)Cu-BaMaSarl-exendin-4, which could be caused by polyvalency effect. The receptor specificity of these probes was confirmed by effective blocking of the uptake in both tumor and normal positive organs with 20-fold excess of unlabeled exendin-4. In conclusion, sarcophagine cage conjugated exendin-4 demonstrated persistent and specific uptake in INS-1 insulinoma model. Dimerization of exendin-4 could successfully lead to increased tumor uptake in vivo. Both (64)Cu-BaMalSar-exendin-4 and (64)Cu-Mal2Sar-(exendin-4)2 hold a great potential for GLP-1R targeted imaging.

The synthesis and single-crystal x-ray structure determination of two new trinuclear metal complexes is detailed. In these we utilise the appended iminodiacetate substituents, in [Co(CH3)NH(CH2CO2H)2sar]3+, to act as a focus for coordination of other metal ions. Thus, we have made complexes of Cu and Ni utilising the basic carbonates of these metals and [Co(CH3){N(CH2CO2H)2}sar]3+ (CoL2) which gave rise to ((CoL2–2H+)2M), M = Cu and Ni. The electrochemical study of the latter was inconclusive and provides the impetus for further study.

Due to the shortage of established platforms/methods for multimodality probe construction, in this study, we developed a heterofunctional chelator, BaAn(Boc)Sar, from sarcophagine cage as a general platform for dual-modality probe construction.A dual-modality probe for positron-emission tomography (PET) and fluorescence imaging was synthesized using the developed BaAn(Boc)Sar chelator. The c(RGDyK)(2) peptide (denoted as RGD(2)) and fluorescence dye Cy5.5 were conjugated with BaAn(Boc)Sar to form BaAnSar-RGD(2)-Cy5.5. Then, BaAnSar-RGD(2)-Cy5.5 was labeled with (64)Cu in ammonium acetate buffer. PET and fluorescent imaging were carried out to evaluate (64)Cu-BaAnSar-RGD(2)-Cy5.5 in nude mice bearing U87MG glioblastoma xenograft.The BaAnSar-RGD(2)-Cy5.5 was labeled with (64)Cu very efficiently in 0.1 M NH(4)OAc buffer within 10 min at 37 °C in the yield of 86.7 ± 4.4 % (n = 3). The specific activity of (64)Cu-BaBaSar-RGD(2) was controlled at 50-200 mCi/μmol for the consideration of both PET and optical imaging. MicroPET quantification analysis shows that the U87MG tumor uptake is 6.41 ± 0.28, 6.51 ± 1.45, and 5.92 ± 1.57 %ID/g at 1, 4, and 20 h postinjection, respectively. Good correlation was obtained between the tumor to muscle ratios measured by the radioactivity and fluorescence intensity. As a proof of concept, an animal surgery study demonstrated that this dual-modality probe would greatly benefit the patients because the PET moiety could be used for tumor detection, and the fluorescent moiety would allow image-guided surgery.Our findings demonstrated the effectiveness and feasibility of preparing dual-modality imaging probes based on the sarcophagine scaffold. The resulting PET and fluorescent imaging probe also holds a great potential for clinical translation.

Purpose We and others have reported that Sarcophagine-based bifunctional chelators could be effectively used in the syntheses of (64)Cu radiopharmaceuticals. The resulted (64)Cu-Sarcophagine complexes demonstrated great in vivo stability. The goal of this study was to further derivatize Sarcophagine cage with amino and maleimide functional groups for conjugation with bioligands.Methods Starting from DiAmSar, three novel chelators (AnAnSar, BaMalSar, and Mal(2)Sar) with two functional groups have been synthesized. Among those, BaMalSar and Mal(2)Sar have been conjugated with cyclic peptide c(RGDyC) (denoted as RGD) and the resulted conjugates, BaMalSar-RGD and Mal(2)Sar-RGD(2) have been labeled with (64)Cu. The tumor targeting efficacy of (64)Cu-labeled RGD peptides were evaluated in a subcutaneous U87MG glioblastoma xenograft model.Results The conjugates, BaMalSar-RGD and Mal(2)Sar-RGD(2) could be labeled with (64)CuCl(2) in 10 min with high purity (98%) and high radiochemical yield (90%). Both (64)Cu-BaMalSar-RGD and (64)Cu-Mal(2)Sar-RGD(2) exhibited high tumor uptake and tumor-to-normal tissue ratios.Conclusion Three novel chelators with two functional groups have been developed based on Sarcophagine cage. The platform developed in this study could have broad applications in the design and synthesis of( 64)Cu-radiopharmaceuticals.

Co(III) sarcophagine-type cage molecules, [Co(diCLsar)](3+) or [Co(HONOsar)](3+), form either 1 : 1 or 1 : 2 host-guest inclusion complexes with mono-phosphonium cations and sodium p-sulfonatocalix[4]arene in the solid state yielding complex I [p-sulfonatocalix[4]arene·Co(diCLsar)·2{benzyltriphenylphosphonium}], complex II [2{p-sulfonatocalix[4]arene}·Co(diCLsar)·3{tetraphenylphosphonium}] and complex III [p-sulfonatocalix[4]arene·Co(HONOsar)·tetraphenylphosphonium]. The diversity of the structural types of these multi-component systems, including the orientation of the Co(III) molecules in the cavities of the calixarenes, depends on the nature of their terminal functional groups. The secondary coordination interactions binding between the Co(III) molecules and p-sulfonatocalix[4]arene have also been investigated in water using NMR techniques.

A new strategy has been developed to attach N-methylpyridine and its derivatives simply and directly to the CoIII sarcophagine cage frame (sar = 3,6,10,13,16,19-hexaazsbicyclo[6.6.6]icosane).

The development of a PET/optical imaging system is attractive because of the opportunity to obtain complementary data from two similar contrast mechanisms using one probe. Different from PET/CT or SPECT/CT, a linker is generally needed to efficiently incorporate PET tag, optical tag, and the biomarker together. Previously we developed a dicarboxyl-functionalized chelator (BaBaSar) derivatized from sarcophagine cage (denoted as Sar). BaBaSar has been used for 64Cu radiopharmaceutical development and the great in vivo stability of 64Cu-BaBaSar encouraged us to continue to derivatize the sarcophagine core for versatile conjugation styles with biomarkers. In this study, we synthesized a hetero-functionalized sarcophagine named BaAnSar: carboxyl group at one end of the Sar cage and amino group on the other end. The pendant hetero-arm could be further conjugated to multiple targeting ligands via biologically stable amide bonds. In order to prove the advantage of the this BaAnSar chelator, we chose dimeric c(RGDyK) peptide (denoted as RGD2), a well-known ligand targeting integrin αvβ3, onto the carboxyl side and fluorescent dye Cy5.5 on the amino functional side of the Sar cage. After labeling with 64Cu, a dual-modality probe, 64Cu-BaAnSar-RGD2-Cy5.5 was made and evaluated in U87MG tumor bearing nude mice. Both NIR fluorescence imaging and microPET clearly delineated the U87MG tumor from the surrounded normal tissue at 1, 4, and 20 h post injection of 64Cu-BaAnSar-RGD2-Cy5.5. The microPET quantification of U87MG tumor uptake was determined as 6.41 ± 0.28, 6.51 ± 1.45, and 5.92 ± 1.57 %ID/g at 1, 4, and 20 h post injection, respectively. Good correlation was also observed between the results measured by ex vivo PET and NIRF organ imaging. In conclusion, we have successfully developed a bifunctional chelator for dual PET and NIRF imaging probe construction. The BaAnSar chelator developed herein has the potential to enhance resolution for comprehensive visualization of the probe distribution and provides a rapid and efficient imaging method for basic research and potential clinical applications, especially as a visual guide during surgery. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5731. doi:1538-7445.AM2012-5731

The generation of amphiphiles derived from macrobicyclic hexamines of the "sarcophagine" class can be prepared through efficient and selective reactions involving the reductive alkylation, using long-chain aldehydes, of amino-functionalised sarcophagines when bound to Cu(ii) or Mg(ii). The Mg(ii) pathway is particularly convenient for the ultimate isolation of the free ligands, which can then be used to form metalloamphiphiles with a variety of metal ions. Structural studies have been made of one of the free (protonated) ligands and some of their complexes.

Copper-64 shows promise as both a suitable PET imaging and therapeutic radionuclide due to its nuclear characteristics. Stable attachment of radioactive (64)Cu(2+) to targeted imaging probes requires the use of a bifunctional chelator. Sarcophagine (Sar) ligands coordinate the metal ion (64)Cu(2+) within the multiple macrocyclic rings comprising the cage structure, yielding extraordinarily stable complexes that are inert to dissociation of the metal ion in vivo. Several (64)Cu labelled RGD derivatives have been applied in imaging of the alpha(nu)beta(3) integrin receptor expression during tumour angiogenesis. In order to design and develop novel molecular imaging probes containing RGD and Sar ligands, we designed a novel versatile Sar cage-like bifunctional chelator named AmBaSar, synthesized using a conventional synthetic strategy. Conjugation with the cyclic peptide RGD, and subsequent labelling with (64)Cu, provided a new PET probe (64)Cu-AmBaSar-RGD for imaging the alpha(nu)beta(3) integrin receptor.

Dimethyl oxalate reacts with 3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]eicosane (sarcophagine) 1 to give oxamide 2 which subsequently is transformed into heptacyclic orthoamide 3.

A new strategy has been developed to attach N-methylpyridine and its derivatives simply and directly to the CoIII sarcophagine cage frame (sar = 3,6,10,13,16,19-hexaazsbicyclo[6.6.6]icosane).

1. 1. A study has been made of the physiological relationships between β-alanine, tyrosine and a naturally occurring dipeptide, β-alanyl- l -tyrosine (sarcophagine), in the fly Sarcophaga bullata . 2. 2. The rate of sarcophagine biosynthesis in the growing larva is about 0·03 μmole/larva per hr, and this accounts for some 40 per cent of the total free β-alanine turned over. In the fully grown larva the dipeptide is the principal non-protein, ninhydrin-positive material, and it sequesters up to 90 per cent of the non-protein β-alanine and tyrosine. 3. 3. During hardening and darkening of the fly puparium, the concentration of sarcophagine and free tyrosine drops precipitously. The observed decrease in peptide-linked and free β-alanine at this time is accounted for quantitatively by the β-alanine bound in the sclerotized puparium. None of these changes occurs in the posterior portions of larvae ligatured behind the brain to prevent pupation. 4. 4. The question of whether the intact dipeptide or its individual hydrolysis products are incorporated into the sclerotized puparium is discussed; the bulk of the evidence suggests that hydrolysis precedes utilization.

The larvae described in this paper were obtained in 1916 by Major C. E. Southon, I.M.S., from a case of intestinal myiasis observed by him in Nairobi (British East Africa). These larvae were sent to Professor J. H. Ashworth and referred to me by Dr G. A. K. Marshall of the Imperial Bureau of Entomology.

An attempt has been made to characterize the synanthropic trends in Sarcophaginae of three Central European cities, viz. Brno, Bratislava and Budapest. The polar ordination of both sarcophagine taxa and of their taxocenoses revealed clear-cut trends towards culturophily and synanthropy in the male preconnubial aggregations of Sarchophaginae evidencing that this group of high Diptera represent an excellent model for the study of this phenomenon.