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SSG-AMP-1 pcbs have arrived, in testing/modification phases.
this is the schematic that I found, sorry I cant seem to get the PDF to have the correct orientation.
All of the transistors are okay, I replaced R77, R79 tested unharmed.
When you say current limiting bulb, is this just a bulb with a lead off of each contact to act as a dummy load?
When you say output rail, is that the terminal strip that connects to the speaker fuse?

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Cyril Dum Nwite, an aide of Rivers state governor, Nyesom Wike, has been arrested with fake police and military uniforms.
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Video showing Gov Nyesom Wike's SA on Special projects Cyril Dum Nwite been paraded after his arrest, alongside four other boys with fake police and military uniforms in Bori.
Posted by Sahara Reporters on Saturday, March 19, 2016


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Originally Posted by abasit Refer to Datasheet for formal definitions of product properties and features. I am already running into some problems. Summary Still, nice to replace an outdated driver. Reply to this review Was this review helpful? Intel stopped writing drivers for this chipset after Vista came out because it wouldn't run Aero in Win7. Used for end of life products.
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Thank you for your feedback. Login or create an account to post a review. In addition, certain chipsets may be implemented in motherboards with different processor packages, much like how the FX could be used either with a Pentium Pro Socket 8 or Pentium II Slot 1.
PC Based Instrumentation and Control. Retrieved 5 November Safari Chrome IE Firefox. Grapihcs will then scan your computer ijtel identify any problem drivers.
Select type of offense: Intel Authorized Distributors sell Intel processors in clearly marked boxes from Intel. Refer to Datasheet for thermal solution requirements.
Listing of RCP does not constitute a formal pricing offer 82910mgl Intel. Your old drivers can even be backed up and restored in case any problems occur. Cons I needed a resolution of X but the nearest 1.
Check directly with your computer manufacturer to determine what graphics controller your computer uses so the grsphics driver can be installed. There are two methods to identify the integrated graphics controller hardware in your computer.
Thermal Design Power TDP represents the average power, in watts, the processor dissipates when operating at Base Frequency with all cores active under an Intel-defined, high-complexity workload. Socket LGA Page 1 of 3. Please work with your appropriate Intel representative to obtain a formal intdl quotation.
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The design of the older graphics controllers finalized before Microsoft released details and specifications on WDDM drivers along with the Aero user interface. Contact your OEM or reseller for warranty support. Intel Graphics Media Accelerator Driver.
Similar help and support threads. Find More Posts by stormy I went to the Intel website, but I found this: The time now is Contact Us Legal Privacy and cookies. The Z68 chipset which supports CPU overclocking and use of the integrated graphics does not have this graphixs bug.
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Always read the motherboard manual and check for BIOS updates. Originally Posted by abasit Use of the Software in conjunction with non-Intel component products is not licensed hereunder.
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Try this – Microsoft Update Catalog. It is a bit driver. Can I use a Windows Vista driver for the integrated graphics? You will receive a reply within 2 business days.


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Further strains were added to U.S. & China relations as China came out on Friday saying they're looking to impose new national security legislation in Hong Kong. This caused oil and equity markets to tumble as this brought a fresh
cloud on the economic recovery prospects.
China also dropped its annual growth target for the first time, adding to uncertainty about the fallout from the COVID-19 pandemic, boosting safe-haven investments such as U.S. Treasuries US10YT=RR and the dollar.
China said it would impose new national security legislation on Hong Kong, leading President Donald Trump to warn that Washington would react "very strongly" against any attempt to gain more control over the former British colony.
Emerging market shares slid -2.72%. Stocks in Europe closed mostly flat and on Wall Street finished mixed as investors prepared for a long weekend in the United States, the UK and elsewhere.
After trading lower most of the session, Wall Street trended upward in late trading, with the S&P and the Dow managing to finish higher.
Tensions between the world's two largest economies have risen in recent weeks, with Washington ramping up criticism of China over the origins of the coronavirus pandemic, raising fears the rhetoric could crimp economic growth.
The U.S. Commerce Department said late in the session that it is adding 33 Chinese companies and other institutions to a blacklist for human rights violations and to address U.S. national security concerns.
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Orangeburg City Council on Tuesday agreed to require individuals to wear face coverings in retail and food service establishments.
The new rules will go into effect at 6 a.m. Friday, July 3.
The ordinance will expire in 61 days, unless it is extended by council.
"I think this is a real opportunity for Orangeburg to lead by example," City Administrator John Yow said. "I hope we will look back 60 days from now and look at our numbers, and our numbers will be much improved in Orangeburg and across South Carolina."
People who violate the ordinance will be guilty of a civil infraction, and assessed a fine of no more than $25. Each violation will be treated as a separate offense.
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Why Pay Retail? Call us or click for a quick quote and save money!
Dates & Prices
|Start Date
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|Mar 21, 2021
|Mar 27, 2021
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|Apr 04, 2021
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|May 23, 2021
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Group Discount - The more the merrier
Promotion Details
Discounts apply to land only pricing, per person, and may vary by departure date. Valid for private group and shared group vacations. Not combinable with any other CIE Tours offers or discounts. Offer may be withdrawn at any time, and is subject to availability. Other conditions may apply. Additional restrictions may apply.
Tour Itinerary
Day 1: Venice Arrival | Welcome Dinner
Meet your tour director at 4:00 PM for a welcome reception and take a one-hour orientation walk around the city known as the 'Queen of the Adriatic.' Spend a couple of hours exploring on your own before gathering again for an ample dinner with your fellow travelers. (D)
Day 2: Venice Walking Tour | Doge's Palace | St. Mark's Basilica | Gondola Ride
Take a guided walking tour of Venice, 'La Serenissima,' the most serene of cities, with its glorious architecture, and its charming bridges and canals. Visit the magnificent Doge's Palace and the acclaimed Piazza and Basilica of San Marco. Journey along the canals for a view of the city from a gondola. Delight in an evening of exploring and dinner on your own. (B)
Day 3: Venice to Florence | Free time in Bologna | Florence dinner
Take a water taxi from your hotel to your coach and travel on to Florence. During your journey you'll stop for free time and lunch on your own at the lively historic foodie city of Bologna. Arrive at your hotel outside Florence's city center. Take a break, then depart for an orientation tour and enjoy some free time in this beautiful city, the capital of Tuscany, and the birthplace of the Renaissance. Enjoy a typical Tuscan dinner with your group at a local Florence restaurant. (B, D)
Day 4: Florence Walking Tour | Accademia Gallery with Michelangelo's David
Take a walking tour of Florence and marvel at the sights of the city center such as the Duomo, Piazza Vecchio, and Piazza della Signoria. Visit the Accademia Gallery to see Michelangelo's iconic sculpture of David. Savor a local lunch in the heart of Florence, where the sauce is handcrafted with locally-sourced tomatoes. After lunch you'll have the rest of the day to explore this magnificent city at your leisure. (B, L)
Day 5: Florence to Rome | Orvieto Local Wine Tasting | Roman Colosseum
They say that all roads lead to Rome, so you're off to the Eternal City with a special and delicious stop in Orvieto for a local wine tasting. Visit the historic Colosseum, the iconic structure of imperial Rome constructed between 72 and 80 AD. This engineering marvel could hold between 50,000 - 80,000 spectators of public spectacles, gladiator battles, and classical dramas. Imagine the ghosts of the Caesars in the ruins of the Forum, the ancient heart of the Roman Empire. Your hotel tonight is in Rome's historic center. (B)
Day 6: Independent Exploration | Vatican Tour with Sistine Chapel | St. Peter's Basilica
The morning is yours to discover Rome in your own way. Enjoy some free time for lunch before your visit to the Vatican with a guided tour of the Museums with entrance to the Sistine Chapel and St. Peter's Basilic (NOTE: The Sistine Chapel and St. Peter's Basilica are subject to occasional closure by the Vatican. Itinerary timing could change on this day due to Vatican availability). Then it's off to your farewell dinner in a charming Roman neighborhood. (B, D)
Day 7: Tour Ends in Rome
Your tour ends after breakfast. (B) Insider tip: You can book pre-nights in Venice or post-nights in Rome if you want to extend your vacation! We've negotiated special rates with our hotels to make booking extra nights easy and affordable. B: Breakfast; L: Lunch; D: Dinner >
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Question: How many suitcases can I take with me on my trip?
Question: Is Airfare Included in the Price?
Similar Tours Other Travelers Liked
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The trip was wonderful. This is our second CIE tour and totally enjoyed both and highly recommend.
Fantastic trip, more than I was expecting.
We greatly enjoyed this tour. The itinerary covered a lot of fabulous places to see, the accommodations were excellent, and the tour guide/coach driver was very entertaining and informative. We will definitely consider CIE and Affordable Tours in booking our next vacation. Thanks!
I expected more hands on guidance in the choice of pubs, more going as a group. However I liked very much our driver/guide, Matt Nolan. His manner was very pleasant, his introductions to the areas we visited and history talks were just enough, and he was skilled driver on the narrow roads. Time on the bus was calm and quiet which seemed to suit us. He managed all the travel details professionally.
Great tour, Highly recommended!
Exceeded my expectations. Wonderful accommodations, very interactive experience with the tour stops.
Wonderful experience, we are looking forward to booking another tour.
Price very reasonable. Nice accommodations. Great tours and good amount of free time.
It was a great experience from beginning to end.
I would highly recommend CIE Tours. The tour, accommodations and food were excellent. Our driver, David, was the best!
2nd trip with CIE. both were up to expectations. good drivers and guides. good selection of places to tour.
This was a great tour with lots of included activities. CIE was very accommodating and helpful.
CIE is a very solid tour company. This was our third trip with CIE and we have toured with five other companies, all well known. CIE is not the cheapest, but the quality is excellent and there are no optional excursions. Everything is included in the price. This means they stick to popular tour options. Optional excursions offer the chance to customize the tour or to opt out of some selections. There were no CIE scheduled attractions that we would have left out. Service and organization were very sound as always.
Our driver/ guide, Murt, made the whole experience very enjoyable. He had a great sense of humor, provided interesting stories & historical events and gave us the best amount of time each day to see all the events on our schedule.
CIE was great. Tour Director was wonderful.
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text:
signed first edition
1920 · Edinburgh
by Park, Willie
Edinburgh: J. & J. Gray & Company, 1920. First edition of the author's rare book on putting. Octavo, original cloth, top edge gilt, illustrated with plates from photographs. Presentation copy, inscribed by the author on the title page, "To C.A.J. Ament Esq. With Compliments, Willie Park." Housed in a custom half morocco clamshell box. Rare signed an inscribed. Willie Park was one of the top professional golfers of his era, winning The Open Championship twice. Park was also a successful golf equipment maker and golf writer, as one of the first professional players to write an instructors manual. In his later years, Park built a significant career as one of the world's best golf course architects. (Inventory #: 26009)


text:
Hardhat Hustle started as the third year university final project for myself and two team members. It is a multiplayer competitive party game for up to four players designed around a main building mechanic that I prototyped in a previous course. The project consists of multiple maps, characters and game modes and focuses on dynamic and fast-paced multiplayer gameplay with a high level of replayability. Hardhat Hustle won the Griffith University Game of the Year 2020 award, and I personally won the Griffith University Best Game Design 2020 award for my work on Hardhat Hustle.
My role in the project was primarily programming, as I did 100% of the programming involved in the project, including gameplay, UI and multiplayer programming. Additionally I was in charge of game design as the game concept was one I had prototyped previously and had spent time balancing and refining the concept before the final project began. I also functioned as team lead, in charge of all scheduling and work delegation, in addition to other production tasks.
Currently we are still working on Hardhat Hustle with the intention of releasing it commercially at some point in the future. For more information see our Twitter page, or play the game in pre-alpha on Itch.io.


text:
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text:
First Claim
1. A radiopharmaceutical to be applied in positron emission tomography, comprising:
- a radiometal-based radiopharmaceutical agent containing a bifunctional chelator namely a DOTA ligand (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) conjugated to a targeting vector and 43Sc being bound to a chelating agent.
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Accused Products
The radionuclide 43Sc is produced at commercially significant yields and at specific activities and radionuclidic purities which are suitable for use in radiodiagnostic agents including imaging agents. In a method, a solid target having an isotopically enriched target layer prepared on an inert substrate is positioned in a specially configured target holder and irradiated with a charged-particle beam of protons or deuterons. The beam is generated using an accelerator such as a biomedical cyclotron at energies ranging from 3 to about 22. MeV. The method includes the use of three different nuclear reactions: a) irradiation of enriched 43Ca targets with protons to generate the radionuclide 43Scin the nuclear reaction 43Ca (p,n)43Sc, b) irradiation of enriched 42Ca targets with deuterons to generate the radionuclide 43Sc in the nuclear reaction 42Ca(d,n)43Sc, and c) irradiation of enriched 46Ti targets with protons to generate the radionuclide 43Sc in the nuclear reaction 46Ti (p,a) 43Sc.
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4 Claims
- 1. A radiopharmaceutical to be applied in positron emission tomography, comprising:
a radiometal-based radiopharmaceutical agent containing a bifunctional chelator namely a DOTA ligand (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) conjugated to a targeting vector and 43Sc being bound to a chelating agent.
- View Dependent Claims (2)
- 3. A radiopharmaceutical, comprising:
a dose for one positron emission tomography having 43Sc to a radio content of 100 to 500 MBq.
- View Dependent Claims (4)
1 Specification
This application is a divisional of patent application Ser. No. 15/310,864, filed Nov. 14, 2016; which was a § 371 national stage filing of international application No. PCT/EP2015/060014, filed May 7, 2015, which designated the United States; this application also claims the priority, under 35 U.S.C. § 119, of European patent application No. 14168136.1, filed May 13, 2014; the prior applications are herewith incorporated by reference in their entirety.
The present invention relates to a variety of methods for the production of the 43Sc radionuclide and radiopharmaceuticals thereof for use in Positron Emission Tomography.
Positron Emission Tomography (PET), in conjunction with other biomedical imaging methods like X-ray Computed Tomography (CT) or Magnetic Resonance Imaging (MRI), is one of the routinely-used diagnostic molecular imaging methods in nuclear medicine for the visualization of in vivo processes in cardiology, neurology, oncology or immunology.
The most widely-used radionuclide is 18F, having a half-life of 1.83 h, mostly in the form of 2-deoxy-2-(18F)fluoro-D-glucose (FDG). This is due to its nuclear decay properties and its availability, from a constantly growing number of biomedical cyclotrons. 18F-labeled compounds can be synthesized in large quantities in centralized GMP—(Good Manufacturing Practice) certified radiopharmacies and delivered over longer distances to hospitals operating PET centers. 18F is suitable to label small organic molecules, but has some disadvantages in labeling peptides or proteins.
Radiometals are more viable for these kinds of molecules. In recent years 68Ga, obtained from a 68Ge/68Ga radionuclide generator system and having a half-life of 1.13 h, rose in prominence for PET in the form of a number of 68Ga-labeled compounds. Despite the numerous advantages of 68Ga-labeled compounds for PET diagnostics, there are a few relevant drawbacks. Firstly, the relatively short half-life requires each site operating a PET scanner to also set up a radiopharmaceutical production facility, fulfilling all requirements imposed by legislation. Secondly, 68Ge/68Ga-generators are able to provide a limited amount of radioactivity, for a maximum of about two to three patient doses per elution. Furthermore, it has been shown that 68Ga-labeled somatostatin analogues show different affinity profiles for human somatostatin receptor subtypes SSTR1-SSTR5, compared to their 177Lu and 90Y-labeled counterparts used for therapy. As a result, a correct therapy planning and dosimetry of patients, based on 68Ga PET imaging, appears questionable.
To overcome these limitations, it is the objective of the present invention to provide a more appropriate alternative to 68Ga that would require the following properties: a positron-emitting radionuclide with a half-life of several hours; high positron yield but low positron energies (resulting in high PET resolution); a low number of accompanying low-energy gamma-rays (if any) with low intensities; and complex-chemical properties similar to 90Y or 177Lu (used for therapy) to allow its introduction in the diagnostic approach using existing clinically-relevant radiopharmaceuticals. Furthermore, its production should be attained in large activities at a biomedical cyclotron in a cost-effective manner and its chemical isolation accomplished in a short, relatively simple procedure, so that it can be directly used for subsequent labeling reactions.
This aim is achieved according to the present invention by a method for generating 43Sc, wherein one of the following methods is applied:
a) 43Ca(p,n)43Sc, using enriched 43Ca at proton beam energies of 5 to 24 MeV;
b) 42Ca(d,n)43Sc using enriched 42Ca and deuteron beam energies of 3 to 12 MeV, or
c) 46Ti(p,α)43Sc using enriched 46Ti and proton beam energies of 10 to 24 MeV.
These three production paths are viable options to generate the 43Sc radionuclide to the desired extent in terms of volume and purity at a price that is competitive as compared to the aforementioned radionuclides, in particular 18F and 68Ga.
An advantageous method for the first option mentioned above can be achieved by the following production steps:
a) an enriched 43Ca target in the form of CaCO3, Ca(NO3)2, CaF2, or CaO powders or Ca metal having a content of 43Ca of 50% or higher is irradiated with a proton beam thereby turning the 43Ca content into 43Sc;
b) dissolving the irradiated enriched 43Ca target in acidic solution and passing the resulting solution through a first column loaded with DGA resin in order to absorb the 43Sc ions;
c) eluting the absorbed 43Sc ions by rinsing the first column with HCl into a second column loaded with a cation exchange resin, such as either DOWEX 50W-X2 or SCX cation exchange resin in order to sorb 43Sc in the second column; and
d) performing the elution of 43Sc from the second column using NH4-acetate/HCl or NaCl/HCl.
An advantageous method for the second option mentioned above can be achieved by the following production steps:
a) an enriched 42Ca target in the form of CaCO3, Ca(NO3)2, CaF2 or CaO powders or Ca metal having a 42Ca content of 50% or higher is irradiated with a deuteron beam thereby turning the 42Ca content into 43Sc;
b) dissolving the irradiated enriched 42Ca target in HCl and passing the dissolved solution through a first column loaded with DGA resin in order absorb the 43Sc ions;
c) eluting the absorbed 43Sc ions by rinsing the first column with HCl into a second column loaded with a cation exchange resing, such as either DOWEX 50W-X2 or SCX cation exchange resin in order to sorb 43Sc in the second column; and
d) performing the elution of 43Sc from the second column using NH4-acetate/HCl or NaCl/HCl.
In order to recycle the part of the 42Ca or 43Ca which has not been converted into 43Sc after the irradiation, the following steps can be applied:
a) an effluent from the first column comprising the valuable enriched Ca isotope in question, is evaporated to dryness in order to form a resultant residue;
b) the resultant residue is dissolved in deionized water and adjusted to a pH of 4.5-5 with ammonia solution and HCl, respectively, in order to form a solution comprising solved Ca(II) ions;
c) the solved content of Ca(II) is precipitated as Ca-oxalate by adding ammonium oxalate solution; and
d) filtering the precipitated Ca-oxalate and transferring the oxalate to the carbonate by slowly heating the filtered Ca-oxalate.
An advantageous method for the third option mentioned above can be achieved by the following production steps:
a) an enriched 46Ti target in form of titania powder is reduced to Ti metal wherein the titania powder having a content of 46Ti of 50% or higher, is irradiated with a proton beam thereby turning the 46Ti content into 43Sc;
b) the irradiated 46Ti target is dissolved in HCl; deionized water is added to dilute the solution to 3 to 5 M HCl;
c) the solution is passed through a first column comprising DGA resin wherein the first column is directly connected to a second column containing SCX cation exchange resin thereby sorbing the 43Sc on the SCX resin; and
d) the sorbed 43Sc is eluted from the SCX column with SCX-Eluent (NaCl/HCl).
Correspondingly, a radiopharmaceutical to be applied in positron emission tomography comprises a radiometal-based radiopharmaceutical agent containing a bifunctional chelator such as a DOTA ligand (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) conjugated to a targeting vector (e.g. antibody, peptide, nanoparticle, vitamin and their derivates) and 43Sc being bound to the chelating agent. Preferably, this radiopharmaceutical comprises 43Sc to a radio content of 100 to 500 MBq, preferably about 200 MBq, for a dose for one positron emission tomography.
Other features which are considered as characteristic for the invention are set forth in the appended claims.
Although the invention is illustrated and described herein as embodied in a production of 43sc radionuclide and radiopharmaceuticals thereof for use in positron emission tomography, it is nevertheless not intended to be limited to the details shown, since various modifications and structural changes may be made therein without departing from the spirit of the invention and within the scope and range of equivalents of the claims.
The construction and method of operation of the invention, however, together with additional objects and advantages thereof will be best understood from the following description of specific embodiments when read in connection with the accompanying drawings.
In search for such a longer-lived, positron-emitting radionuclide, the present invention identifies 43Sc as a more appropriate candidate than 68Ga, with chemical properties more similar to Y and the lanthanides and, thus, a more appropriate match than its Ga counterpart. The radioactive decay of 43Sc occurs with a low average positron energy of 0.476 MeV (68Ga: 0.830 MeV), a high total positron yield of 88.1% (68Ga: 88.9%), and an ideal half-life of 3.89 h (68Ga: 1.13 h), thereby, allowing its transport over long distances to the costumer (i.e. >500 km). Its decay is associated with a relatively low energy gamma-ray of 373 keV and 23% abundance (68Ga: 1077 keV, 3.2%), which will not influence PET imaging negatively, as modern PET scanners can be operated using a relatively narrow energy window (i.e. 440-665 keV). As a result, this radionuclide has the potential to overcome the abovementioned limitations of 68Ga, while offering superior properties. Scandium is known to form complexes with very high stability constants with DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), a widely-used chelator for radiometals in radiopharmaceutical chemistry. The stability constants are comparable to lutetium or yttrium as they all form complexes with square-antiprismatic geometry, whereas they are lower for gallium with distorted octahedron geometry. 68Ga can, therefore, easily be exchanged with 43Sc in radiopharmaceuticals employing the DOTA chelator and can be introduced directly into a GMP-compliant cassette labeling system, such as one provided by Eckert & Ziegler for the labeling of DOTA-ligands in the form of DOTA-TATE, DOTA-TOC, DOTA-BASS, DOTA-PSMA, DOTA-Folate etc.
The present invention also describes a variety of methods for the production of 43Sc, in sufficient quantities and high radionuclidic purity, by means of a biomedical cyclotron, i.e. with proton beams in the energy range of 10-24 MeV (or deuteron beams in the energy range of 3 to 12 MeV).
The present invention also describes the required radiochemical procedures to extract 43Sc from its target material in quality and quantity suitable for direct labeling reactions and for future medical application. In addition, procedures to recover the valuable, enriched target materials are disclosed.
Radiopharmaceuticals comprising metallic radionuclides are gaining in importance in diagnostic and therapeutic nuclear medicine. A prime example is 99mTc, which is currently the most widespread metallic diagnostic radionuclide in nuclear medicine and recently gained attention due to a worldwide supply crisis. The search for alternative procedures is of utmost importance. Examples of therapeutic metallic radionuclides are 90Y used in Zevalin® (Ibritumomab tiuxetan labeled with 90Y), 177Lu in Lutathera® also known as 177Lu-DOTA-TATE (177Lu-DOTAO-Tyr3-Octreotate; 177Lu-DOTA-DPhe-c(Cys-Tyr-DTrp-Lys-Thr-Cys)-Thr; DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra-acetic acid), or even 223Ra (223RaCl2) in Xofigo® for the treatment of patients with prostate cancer and bone metastases.
In recent years, somatostatin-receptor-targeted radionuclide therapy of neuroendocrine tumors (NET) has gained much attention. Therapies using 90Y and 177Lu have proven so successful that the International Atomic Energy Agency (IAEA), in cooperation with EANM and SNMMI, has recently issued a practical guidance on peptide receptor radionuclide therapy (PRRNT) for NET. PRRNT was first administered in 1996 in Basel, Switzerland. Other therapies targeting G-protein coupled receptors with peptides, the folate receptor or using monoclonal antibodies conjugated to suitable metallic radionuclides are currently in pre-clinical and clinical trials or are already licensed as radiopharmaceuticals. Quite often, these pharmaceuticals can also be labeled with a relatively short-lived diagnostic radionuclide, especially if the pharmacokinetics is fast. Central to research efforts are isotopes of elements that offer ideal radionuclidic pairs for diagnostic and therapeutic purposes (theranostics or theragnostics). In this way, the same pharmaceutical entity could be labeled with either a diagnostic or a therapeutic nuclide and, due to negligible isotopic effects, one can assume that the therapeutic effect will take place in the positions previously identified by imaging. There is hope that such an approach will facilitate the correct therapy planning and dosimetry of patients, a problem which has not effectively been solved to date.
An inspection of the chart of nuclides reveals that very few such "matched pairs" exist, especially if one requirement is that the diagnostic radionuclide must be suitable for PET. No suitable matched positron emitter exists for the two most widely-employed therapeutic radio-nuclides in PRRNT, 90Y and 177Lu (86Y with a low positron branch of 31.9% and numerous high-intensity, high-energy gamma-rays cannot be considered as particularly suitable without the application of correction methods and also concerning radiation dose to patients and personnel, but has been used in patients nonetheless).
Therefore, radionuclides that behave similarly chemically, resulting in comparable biological behavior, should be taken into consideration. Recently, the diagnosis of NET was successfully performed using 68Ga-radiolabeled derivatives of octreotide. 68Ga is obtained from a 68Ge/68Ga radionuclide generator system and has a half-life of 1.13 h. While diagnostic results are far superior to Single-Photon Emission Computed Tomography (SPECT) of 111 In-radiolabeled derivatives, there are drawbacks to using 68Ga. The relatively short half-life requires each site operating a PET scanner to also set up a radiopharmaceutical production site, fulfilling all new requirements imposed by legislation related to GMP. Furthermore, current 68Ge/68Ga radionuclide generator systems are limited to about 2 GBq of activity, which results in the production of not more than two to three patient doses per generator elution. The half-life of 68Ge (270.82 d) requires an annual replacement of the generator, at best. The current system makes 68Ga-labeled radiopharmaceuticals and its required infrastructure labor-intensive and, thus, is seen as an expensive application, as experienced by the applicants'"'"' recent introduction of 68Ga-DOTA-TATE.
Compared to e.g. 18F-labeled compounds that can be synthesized in GMP-certified radiopharmacies and delivered to hospitals operating PET centers over further distances, the abovementioned drawbacks of 68Ga may limit the widespread application of this radionuclide for PET imaging. Furthermore, it has been shown that 68Ga-labeled somatostatin analogues show different affinity profiles for human somatostatin receptor subtypes SST1-SST5, compared to their 177Lu and 90Y counterparts used for therapy. As a result, a correct therapy planning and dosimetry of patients based on 68Ga imaging appears questionable.
Taking the abovementioned statements into account, 44Sc-radiolabeled radiopharmaceuticals were considered as an alternative, especially since the chemical behavior of Sc is expected to be more similar to Y and Lu than its Ga counterpart. This radionuclide, with an attractive half-life of 3.92 h, can be obtained from a 44Ti/44Sc radionuclide generator system, or be produced at a 10-20 MeV biomedical cyclotron via the 44Ca(p,n)44Sc nuclear reaction, producing a much greater yield than extracting it from a generator.
The only serious drawback of 44Sc as positron-emitting radionuclide is the co-emission of an 1157 keV gamma-ray with 99.9% intensity. Compton scattered gamma-rays can interfere with the correct reconstruction of the location of the annihilation reaction of the positron and, thus, impair the obtained PET image. The high-energy gamma-ray also adds to the radiation exposure of patients and personnel. Nevertheless, it should be mentioned that the co-emitted 1157 keV gamma-ray of 44Sc was used for "3γ imaging" using detection of β+γ coincidences with liquid xenon as detection medium. The first human patient was diagnosed by administrating 37 MBq of 44Sc-DOTA-TOC (44Sc-DOTAO-Tyr3-octreotide; 44Sc-DOTA-DPhe-c(Cys-Tyr-DTrp-Lys-Thr-Cys)-Thra(ol)). High-quality PET/CT images were recorded even 18 h post injection (p.i.), demonstrating that the uptake kinetics can be followed over a relatively long period compared to the 68Ga-labeled analogue and that an individual dosimetry of a subsequent therapeutic application with a longer-lived 90Y- or 177Lu-analogue may be possible.
The biomedical cyclotrons used mainly for 18F production are designed to accelerate protons and, quite often, also deuterons. According to the present invention, three nuclear reactions using a biomedical cyclotron are used to produce clinically-relevant activities of 43Sc. The reactions proposed are:
a) 43Ca(p,n)43Sc, using commercially available, enriched 43Ca (natural abundance 0.153%) at proton beam energies of 5 to 24 MeV;
b) 42Ca(d,n)43Sc, using commercially available, enriched 42Ca (natural abundance 0.647%) and deuteron beam energies of 3 to 12 MeV, or
c) 46Ti(p,α)43Sc, using commercially available, enriched 46Ti (natural abundance 8.25%) and proton beam energies of 10-24 MeV.
Due to the relatively low beam energies, the production of 43Sc can be established at most biomedical cyclotrons equipped with a solid target station, resulting in an overall cost reduction due to centralized production. Due to its longer half-life, 43Sc-radiopharmaceuticals can be produced concurrently or ahead of 18F-labeled ones and shipped together to the customer.
The present disclosure describes the 43Sc production using different production routes and establishes the most appropriate one such that the product can be used for the labeling of compounds for clinical evaluation. Different 43Sc-labeled DOTA-peptides, based on ligands binding mainly to SSTR2, are compared to the 177Lu, 90Y, and 68Ga-labeled counterparts with respect to binding affinity, internalization, stability and in vivo properties.
43Sc can be produced at a biomedical cyclotron using three different production routes, which will be discussed in more detail. Its production using an α-particle beam in the reaction 40Ca(α,n)43Ti→β+→43Sc is an option, however, accelerators which are able to deliver α-particle beams are scarce and more expensive to operate. Furthermore, the active target thickness is much more limited with α-particle beams significantly reducing the overall production yield.
As a result, the 43Ca(p,n)43Sc, 42Ca(d,n)43Sc, or 46Ti(p,α)43Sc reactions are considered. The TENDL-2013 calculations, a TALYS-based evaluated nuclear data library, were used to estimate the activity and the radionuclidic purity that could be obtained by irradiation of commercially-available enriched target materials. Where available, the predicted TENDL-2013 calculations were compared with experimentally-determined production reaction cross sections. It was assumed that 10 mg/cm2 of the enriched target element were irradiated at a beam energy corresponding to the maximum of the predicted excitation function over two hours and an intensity of 25 μA. After the irradiation, an one-hour waiting period is considered before chemical processing and a processing time of one hour including the labeling of a pharmaceutical. Assuming an 85% chemical yield of the Sc/Ca separation and an 85% yield of the labeling procedure, the theoretical product yields listed in Table 1 can be expected under the aforementioned conditions. These yields were based on the following isotopic compositions of commercially available, enriched target materials:
40Ca (28.50%), 42Ca (1.05%), 43Ca (57.9%), 44Ca (12.36%), 46Ca (<0.003%), 48Ca (0.19%)
40Ca (17.79%), 42Ca (80.80%), 43Ca (0.39%), 44Ca (0.97%), 46Ca (<0.01%), 48Ca (<0.05%)
46Ti (96.9%), 47Ti (0.45%), 48Ti (2.32%), 49Ti (0.17%),50Ti (0.16%)
The 43Ca(p,n)43Sc nuclear reaction:
The calculated maximum of the excitation reaction corresponds to about 388 mb (10-27 cm2) at a beam energy of 9 MeV. The calculated cross sections are in reasonable agreement with experimental data and the applicants'"'"' own measurements. As can be seen from Table 1, the yield of 2 GBq 43Sc is good, however, co-production of 44gSc is significant. Considering the fact that 44gSc has an almost identical half-life and was discussed as a suitable PET nuclide, all other Sc nuclides contribute <0.12% of the total Sc activity, with the long-lived 46gSc comprising only <2.1×10-5% of the total activity.
The 42Ca(d,n)43Sc Nuclear Reaction:
The calculated maximum of the excitation reaction corresponds to about 280 mb (10-27 cm2) at a beam energy of 5 MeV. The yield of 2 GBq of 43Sc is good and the co-production of 44gSc is <1%. In relation to 43Sc+44gSc, all other Sc radionuclides contribute <0.11% of the total Sc activity, the largest contributor being 49Sc with a half-life of only 57.2 m. The long-lived 46gSc comprises only <3.5×10-6% of the total activity. In maximum production cross sections of only about 80 mb (10-27 cm2) have been reported. Own measurements indicate production cross sections in the range of 125 to 225 mb (10-27 cm2) for beam energies between 3.6 and 7.8 MeV.
The 46Ti(p,α)43Sc Nuclear Reaction:
The calculated maximum of the excitation reaction corresponds to about 31 mb (10-27 cm2) at a beam energy of 16 MeV. The available experimental reaction cross section data is about 40 mb at 16 MeV (renormalized to 100% 46Ti isotopic abundance) and, thus, in reasonable agreement. The yield of 0.2 GBq of 43Sc is lower by one order of magnitude compared to the other two production reactions but the co-production of 44gSc is <1%. In relation to 43Sc +44gSc, all other Sc radionuclides contribute <0.02% of the total Sc activity. The long-lived 46gSc comprises only 3.6×10-4% of the total activity.
A chemical procedure was established for all three nuclear reactions that quantitatively recovers the enriched target materials. Assuming a conservative recovery yield of 80%, the material costs per patient dose (200 MBq 43Sc) are given in Table 1. The current cost of the target materials is as follows: 43Ca 94.50 CHF/mg, 42Ca 54.00 CHF/mg, and 46Ti 13.65 CHF/mg. For comparison, the cost of 68Ga was calculated at 85 CHF/dose, assuming that a generator can be eluted 200 times before breakthrough of 68Ge starts to occur. The abovementioned considerations are provided to demonstrate that the production costs of 43Sc are insignificant compared to the costs of the radiopharmaceutical product, especially taking into account that biomedical cyclotrons are usually only in operation for few hours per day to produce 18F.
Taking the yield of 43Sc and the co-production of 46gSc as long-lived contaminant into consideration, the 42Ca(d,n)43Sc reaction appears, currently, to be most favorable. The 46Ti(p,α)43Sc reaction also delivers a relatively pure product. For this reason, a careful experimental assessment of the cross section was necessary. The 43Ca(p,n)43Sc reaction remains viable, especially if more highly-enriched 43Ca becomes available. It is, therefore, essential to investigate the product spectrum of all three reactions experimentally and to optimize the production of 43Sc in relation to the long-lived 46gSc by optimization of the beam energy.
Targets are prepared by pressing either enriched 42Ca or 43Ca in the form of the metal or in the form of Ca compounds such as CaCO3, Ca(NO3)2, CaF2 or CaO powders or Ca metal into the groove of the target holder. The target holder provides a volume of up to 0.28 cm3 accommodating up to 100 mg of the enriched isotope in question. In the case of Ti targets, the enriched material can only be purchased in the form of TiO2. The rapid dissolution of TiO2 in a hot-cell environment presents serious difficulties, if hot sulfuric acid or concentrated HF were to be avoided. As a result, the enriched Ti target material is first quantitatively reduced to Ti metal. As can be seen from Table 1, the use of about 100 mg enriched 46Ti will result in the production of >10 patient doses per irradiation, thus, making the 46Ti(p,α) reaction a viable option, despite the low production cross section.
A chemical strategy to isolate 43Sc from irradiated target materials in quantity and quality sufficient for radiopharmaceutical applications is provided, including the recovery of the valuable target material in question. The product must be in a chemical form that is directly usable for a subsequent labeling process.
The chemical strategy for the production of 43Sc from enriched Ca target material will be similar to the one established for 44Sc.
Design, manufacturing and irradiation of enriched 42CaCO3 or 43CaCO3 targets:
To manufacture the targets, 10±1 mg enriched 42CaCO3 or 43CaCO3 powder is placed on top of ˜160 mg graphite powder (99.9999%) and pressed with 10 t of pressure. The targets have dimensions of 0.4-0.5 mm thickness and a diameter of 16 mm (the pressed 42CaCO3 or 43CaCO3 powder have a calculated depth of 190 μm and diameter of 6 mm in the center of the disc). The encapsulated 42CaCO3 or 43CaCO3 pressed target is placed in a target holder system before introduction into the irradiation facility (see
A column (1 mL cartridge fitted with 20 μm frit, cut to a length of 27 mm) is filled with ˜70 mg of DGA resin (Triskem International, France) and a 20 μm frit placed on top of the resin. The DGA column is preconditioned with 3 M HCl. A second column is used to concentrate the 43Sc. Two methods can be followed for the concentration of product. Method A: The second column (1 mL cartridge fitted with 20 μm frit) was filled with ˜140 μL of DOWEX 50W-X2 and a 20 μm frit placed on top of the resin. The column is preconditioned with 0.1 M HCl solution. Method B: Alternatively, SCX (Agilent Technologies Inc., USA) cartridges are used for the concentration step, which can be used as purchased without preconditioning.
Separation of 43Sc from Calcium Target Material:
The activated target is removed from its aluminum encapsulation and transferred into a glass vial (reaction vessel), dissolved in 2.5 mL 3 M HCl and loaded onto the DGA column, being passed over a 10 mm long filter (1 mL cartridge fitted with a 20 μm frit) beforehand. The target container is rinsed with 2.5 mL 3 M HCl and the solution passed over the DGA resin. A further 4 mL 3 M HCl is applied directly onto the DGA column to ensure complete removal of residual Ca(II). A system of syringes and three-way valves are used to transfer solutions from outside into the hot cell (
Enriched 42CaCO3 or 43CaCO3 Target Material Recycling:
The effluent from the DGA column of several production runs, containing the valuable enriched Ca isotope in question, is evaporated to dryness. The resultant white residue is dissolved in 20 mL deionized water and adjusted to a pH of 4.5-5 with 2.5% ammonia solution and 1 M HCl, respectively. Ca(II) is precipitated as Ca-oxalate by adding 20 mL 0.3 M ammonium oxalate solution. The mixture is left to stand for 2 hours to ensure complete precipitation, filtered through a porcelain filter crucible (8 μm pore size) and the oxalate transferred to the carbonate by slowly heating to 500° C. Thus, the valuable enriched materials are again available to manufacture targets. A preceding ICP-OES analysis indicated a Ca concentration of 450 ppm, with minor metallic contaminants (2 ppm Al and 1 ppm Sr). An overall recovery yield of 98% was obtained with the ammonium oxalate precipitation method. The recovered target material provided 43Sc of the same quality as was obtained with targets from the originally-purchased 43CaCO3.
The production of 43Sc using the 46Ti(p,α)43Sc reaction requires a separation of Sc from Ti and a recycling step for the enriched 46Ti target material. The chemical separation strategy is based on literature data and ongoing research and development at PSI. With the development of a 44Ti/44gSc generator system, the chemical separation of Ti and Sc has already been the subject of some research efforts.
The chemical separation of Ti and Sc has proven to be difficult, as Ti is easily oxidized and its oxide is only effectively dissolved using hot, concentrated sulfuric acid. A further headache is the fact that extensive heat is required to evaporate the sulfuric acid, as it boils at over 300° C. More recent attempts at separating these two elements involved the use of hydrofluoric acid (HF). HF was used to dissolve the target material, before it was diluted and loaded on an anion exchange resin column. With Ti retained, the eluted Sc (dilute HF and dilute nitric acid) is loaded on to a cation exchange resin and eluted with dilute ammonium acetate. Another system, which involved the separation of 44Ti from Sc target material, saw a concentrated solution of hydrochloric acid being used to pass through an anion exchange resin, allowing the Ti to be retained and the Sc to pass though.
A chemical strategy to isolate 43Sc produced in the 46Ti(p,α) reaction from irradiated Ti target materials in quantity and quality sufficient for radiopharmaceutical applications is provided, including the recovery of the valuable target material in question. The product must be in a chemical form directly usable for a subsequent labeling process.
Reduction of 46TiO2:
Up to 250 mg 46TiO2 are mixed with 40% surplus CaH2, metals basis in an oxygen-free Ar-environment. A tablet is pressed with 5t pressure for 2 minutes and in a molybdenum crucible inserted into an Ar-flooded oven. The oven is heated up to 900° C. in about 30 minutes, and the temperature is kept at 900° C. for 1 hour. The oven is cooled down to 100° C., which takes about 2-3 hours. The reduction is complete when the white TiO2 transformed into black Ti. The tablet is placed on a Millipore-Filter (0.45 μm) in a Büchner funnel and washed with about 20 ml deionized water, whereby the tablet disintegrates. The CaO is dissolved by washing with 100-150 mL acetic acid, suprapur (1:4) over a time period of 3 hours. The filter is rinsed with deionized water until the effluent of the Büchner funnel is pH neutral. The resulting Ti-powder is dried in a desiccator overnight.
Design, Manufacturing and Irradiation of Enriched 46Ti Metal Targets:
The manufacturing of 46Ti metal targets proceeds analogous to the preparation of enriched CaCO3-targets. To manufacture the targets, 10±1 mg enriched 46Ti metal powder is placed on top of ˜160 mg graphite powder (99.9999%) and pressed with 10 t of pressure. The resulting tablet is encapsulated in aluminum and placed in a target holder system.
Preparation of Resin Columns:
A column (1 mL cartridge fitted with 20 μm frit, cut to a length of 27 mm) is filled with ˜70 mg of DGA resin (TrisKem International, France) and a 20 μm frit placed on top of the resin. The DGA column is cleaned and preconditioned with 4 mL 6 M HCl and 9 mL 4 M HCl.
Separation of 43Sc from Titanium Target Material:
The irradiated 46Ti-graphite target is dissolved in 5 mL 6 M HCl at 180° C. for 10 minutes, 2 mL deionized water is added to dilute the solution to 4 M HCl.
The starting solution is passed through the DGA resin column. The vial is flushed with 3 mL 4 M HCl, passed through the resin column, with any remaining impurities removed from the DGA column with an additional 8 mL 4M HCl. The DGA column is directly connected to a second column containing SCX cation exchange resin. 43Sc is eluted from the DGA column with 10 mL 0.05 M HCl and sorbed on the SCX column. Elution of the product from the SCX column with 700 μL SCX-Eluent (4.8M NaCl/0.1 M HCl) yields 43Sc directly available for labeling reactions. The chemical yield of Sc is >98%.
Labeling Reactions:
The product is placed into a Reactivial containing 2 mL 2M sodium acetate buffer and 10 μg peptide (DOTA-chelator). The resultant solution is heated at 100° C. for 10 minutes, after which it is passed through a Sep-Pak C18 Lite cartridge (Waters Corporation, USA). The cartridge is rinsed with 2 mL 0.9% saline, before the product is eluted with 2 mL 50% ethanol. The addition of gentisic acid ensures that no radiolysis of the labeled product occurs.
The applicants believe that 43Sc represents a highly promising radionuclide with unique and important scientific, clinical and industrial implications.


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text: Editing (section) Luis Hontiveros 0 You do not have permission to edit this page, for the following reasons: The action you have requested is limited to users in one of the groups: Users, FANDOM Staff, FANDOM Helpers, Wiki Managers, Content Team Members. Please log in to edit this wiki.Joining Big Brother Wiki is free, and it only takes a minute.We hope that you sign in, and become a member of the community!Click here to log in or create an account more + You can view and copy the source of this page: ==Biography== '''The Longing Son of Taguig''' Enrique Roberto Luis Hontiveros Samonte is a 24-year old ramp model and actor from Taguig. He is a nephew of incumbent Senator Risa Hontiveros. He grew up in a broken family, his dad focused on his first family and he was the only child. He had no communication with his father since his graduation in grade school. Few years ago, Luis discovered in his birth certificate of which he was a second-born child to his mother. Return to Luis Hontiveros. Retrieved from "https://bigbrother.fandom.com/wiki/Luis_Hontiveros" Edit summary Preview Mobile Desktop Show changes


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Norwegian Offshore Wind Cluster is aiming to be the strongest supply chain for floating offshore wind world wide. Norway have a very strong petro-maritime supply chain, well fit to take, and hold this position. Companies like Equinor, Aker Solutions and Kværner are in the forefront already, as a number of other Norwegian based companies. Membership is open for any type of company or organization, international as well.
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Our goal is to increase profits by cooperating on innovation and market opportunities in offshore wind.
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peanut butter. His reply?
"That has no bearing on My reality"
(He prefers crunchy)
It looks like He may have been being sardonic, but i assure you, Dear Reader, He wasn't. The fact that there's only crunchy peanut butter in the house (which i hate) has absolutely no effect on Him. Really, and why should it? Sir's matter-of-fact tone and deadpan delivery reiterated the long-realized concept that what i want, i get only by His desire to give me such. The new epiphany is that sometimes it's not even something worth mentioning.
i was reminded of another exchange, not ironical at all, shortly after Sir collared me. We were debating some topic or another, and every salient point i made was met with "you may be right, but..." Let's say i'm not usually thrilled to be losing a debate. In exasperation, i exclaimed;
"Am i ever going to win with You?!?"
Sir stopped, His eyes bored into mine as He softly replied;
i only felt a little silly as i added 'peanut butter' to my grocery list.