technetium-99m generator

⁹⁹Mo can be obtained by the neutron activation (n,γ reaction) of ⁹⁸Mo in a high-neutron-flux reactor. However, the most frequently used method is through fission of uranium-235 in a nuclear reactor. While most reactors currently engaged in ⁹⁹Mo production use highly enriched uranium-235 targets, proliferation concerns have prompted some producers to transition to low-enriched uranium targets.{{cite report|url=https://www.nap.edu/catalog/12569/medical-isotope-production-without-highly-enriched-uranium|title=Medical Isotope Production Without Highly Enriched Uranium|author=The National Research Council|access-date=20 November 2012}} The target is irradiated with neutrons to form ⁹⁹Mo as a fission product (with 6.1% yield).{{Cite web |url=http://www.doh.wa.gov/ehp/rp/factsheets/factsheets-pdf/fs32mo99.pdf |title=Archived copy |access-date=2 August 2008 |archive-date=24 May 2009 |archive-url=https://web.archive.org/web/20090524051521/http://www.doh.wa.gov/ehp/rp/factsheets/factsheets-pdf/fs32mo99.pdf |url-status=dead }} Molybdenum-99 is then separated from unreacted uranium and other fission products in a hot cell.{{Cite conference |title=Development and Processing Of LEU Targets for Mo-99 Production—Overview of the ANL Program |url=https://www.rertr.anl.gov/MO99/JLS95.html |conference=1995 International Meeting on Reduced Enrichment for Research and Test Reactors|vauthors=Snelgrove L, Hofman GL, Wiencek TC, Wu CT, Vandegrift GF, Aase S, Buchholz BA, Dong DJ, Leonard RA, Srinivasan B|date=18-21 September 1994|location=Paris|osti=146775}}

^99mTc remained a scientific curiosity until the 1950s when Powell Richards realized the potential of technetium-99m as a medical radiotracer and promoted its use among the medical community.{{cite web |last1=Gasparini |first1=Allison |title=Celebrating the 60th Anniversary of Technetium-99m |url=https://www.bnl.gov/newsroom/news.php?a=213162 |website=Brookhaven National Laboratory |date=24 October 2018}} While Richards was in charge of the radioisotope production at the Hot Lab Division of the Brookhaven National Laboratory, Walter Tucker and Margaret Greene were working on how to improve the separation process purity of the short-lived eluted daughter product iodine-132 from tellurium-132, its 3.2-days parent, produced in the Brookhaven Graphite Research Reactor.{{cite web|title=Brookhaven Graphite Research Reactor|url=http://www.bnl.gov/bnlweb/history/BGRR.asp|access-date=3 May 2012|archive-url=https://web.archive.org/web/20130402194012/http://www.bnl.gov/bnlweb/history/BGRR.asp|archive-date=2 April 2013|work=bnl.gov}} They detected a trace contaminant which proved to be ^99mTc, which was coming from ⁹⁹Mo and was following tellurium in the chemistry of the separation process for other fission products. Based on the similarities between the chemistry of the tellurium-iodine parent-daughter pair, Tucker and Greene developed the first technetium-99m generator in 1958.{{cite book|last=Richards|first=Powell|title=Technetium-99m: The Early Days|year=1989|publisher=Brookhaven National Laboratory|location=New York|volume=BNL-43197 CONF-8909193-1|osti=5612212}}{{cite journal|last1=Tucker|first1= W.D.|last2= Greene|first2= M.W.|last3= Weiss|first3=A.J.|last4= Murrenhoff |first4=A.|title=Methods of preparation of some carrier-free radioisotopes involving sorption on alumina|journal=Transactions American Nuclear Society|year=1958|volume=1|pages=160–161}} It was not until 1960 that Richards became the first to suggest the idea of using technetium as a medical tracer.{{cite journal|last=Richards|first=Powell|title=A survey of the production at Brookhaven National Laboratory of radioisotopes for medical research|year=1960|journal=VII Rassegna Internazionale Elettronica e Nucleare Roma|pages=223–244}}{{cite web|url=http://www.bnl.gov/bnlweb/history/tc-99m.asp|archive-url=https://web.archive.org/web/20130402194257/http://www.bnl.gov/bnlweb/history/Tc-99m.asp|archive-date=2 April 2013|work=Bnl.gov|title=The Technetium-99m Generator}}{{cite journal|last1=Richards|first1=P.|last2=Tucker|first2= W.D.|last3=Srivastava|first3= S.C.|title=Technetium-99m: an historical perspective|journal=The International Journal of Applied Radiation and Isotopes|date=October 1982|volume=33|issue=10 |pages=793–9 |pmid=6759417|doi=10.1016/0020-708X(82)90120-X}}{{cite journal|last1=Stang|first1=Louis G.|last2=Richards|first2= Powell|title=Tailoring the isotope to the need|journal=Nucleonics|year=1964|volume=22|issue=1|issn=0096-6207}}

{{see also|Radionuclide generator}}

Technetium-99m's short half-life of 6 hours makes long-term storage impossible. Transport of ^99mTc from the limited number of production sites to radio pharmacies (for manufacture of specific radiopharmaceuticals) and other end users would be complicated by the need to significantly overproduce to have sufficient remaining activity after long journeys. Instead, the longer-lived parent nuclide ⁹⁹Mo can be supplied to radio pharmacies in a generator, after its extraction from the neutron-irradiated uranium targets and its purification in dedicated processing facilities.{{cite journal |first1=Jonathan R.|last1=Dilworth|last2=Parrott|first2=Suzanne J.|title=The biomedical chemistry of technetium and rhenium|journal=Chemical Society Reviews|year= 1998|volume=27|pages=43–55|doi=10.1039/a827043z }} Radio pharmacies may be hospital-based or stand-alone facilities, and in many cases will subsequently distribute ^99mTc radiopharmaceuticals to regional nuclear medicine departments. Development in direct production of ^99mTc, without first producing the parent ⁹⁹Mo, precludes the use of generators; however, this is uncommon and relies on suitable production facilities close to radio pharmacies.{{cite journal |last1=Boschi |first1=Alessandra |last2=Martini |first2=Petra |last3=Pasquali |first3=Micol |last4=Uccelli |first4=Licia |title=Recent achievements in Tc-99m radiopharmaceutical direct production by medical cyclotrons |journal=Drug Development and Industrial Pharmacy |date=2 September 2017 |volume=43 |issue=9 |pages=1402–1412 |doi=10.1080/03639045.2017.1323911|pmid=28443689 |s2cid=21121327 }}

Generators provide radiation shielding for transport and to minimize the extraction work done at the medical facility. A typical dose rate at 1 metre from ^99mTc generator is 20–50 μSv/h during transport.{{cite news|last=Shaw|first=Ken B.|title=Worker Exposures: How Much in the UK?|url=http://www.iaea.org/Publications/Magazines/Bulletin/Bull271/27104592527.pdf|access-date=19 May 2012|newspaper=IAEA Bulletin|date=Spring 1985|url-status=dead|archive-url=https://web.archive.org/web/20110905103646/http://www.iaea.org/Publications/Magazines/Bulletin/Bull271/27104592527.pdf|archive-date=5 September 2011}}

These generators' output declines with time and must be replaced weekly, since the half-life of ⁹⁹Mo is still only 66 hours. Since the half-life of the parent nuclide (⁹⁹Mo) is much longer than that of the daughter nuclide (^99mTc), 50% of equilibrium activity is reached within one daughter half-life, 75% within two daughter half-lives. Hence, removing the daughter nuclide (elution process) from the generator ("milking" the cow) is reasonably done as often as every 6 hours in a ⁹⁹Mo/^99mTc generator.{{cite book |last1=Brant |first1=William E. |last2=Helms |first2=Clyde |title=Fundamentals of Diagnostic Radiology |date=2012 |publisher=Lippincott Williams & Wilkins |isbn=9781451171396 |page=1240 |url=https://books.google.com/books?id=uVeUWa3-1o8C&pg=PA1240 |language=en}}

Most commercial ⁹⁹Mo/^99mTc generators use column chromatography, in which ⁹⁹Mo in the form of molybdate, MoO₄²⁻ is adsorbed onto acid alumina (Al₂O₃). When the ⁹⁹Mo decays it forms pertechnetate TcO₄⁻, which, because of its single charge, is less tightly bound to the alumina. Pouring normal saline solution through the column of immobilized ⁹⁹Mo elutes the soluble ^99mTc, resulting in a saline solution containing the ^99mTc as pertechnetate, with sodium as the counterion.

The solution of sodium pertechnetate may then be added in an appropriate concentration to the pharmaceutical kit to be used, or sodium pertechnetate can be used directly without pharmaceutical tagging for specific procedures requiring only the ^99mTcO₄⁻ as the primary radiopharmaceutical. A large percentage of the ^99mTc generated by a ⁹⁹Mo/^99mTc generator is produced in the first 3 parent half-lives, or approximately one week. Hence, clinical nuclear medicine units purchase at least one such generator per week or order several in a staggered fashion.{{cite book |last1=Hamilton |first1=David I. |title=Diagnostic Nuclear Medicine: A Physics Perspective |date=2004 |publisher=Springer Science & Business Media |isbn=9783540006909 |page=28 |url=https://books.google.com/books?id=rYBlaWbIvq0C&pg=PA28 |language=en}}

When the generator is left unused, ⁹⁹Mo decays to ^99mTc, which in turn decays to ⁹⁹Tc. The half-life of ⁹⁹Tc is far longer than its metastable isomer, so the ratio of ⁹⁹Tc to ^99mTc increases over time. Both isomers are carried out by the elution process and react equally well with the ligand, but the ⁹⁹Tc is an impurity useless to imaging (and cannot be separated).

The generator is washed of ⁹⁹Tc and ^99mTc at the end of the manufacturing process of the generator, but the ratio of ⁹⁹Tc to ^99mTc then builds up again during transport or any other period when the generator is left unused. The first few elutions will have reduced effectiveness because of this high ratio.{{cite journal|last=Moore|first=P.W.|title=Technetium-99 in generator systems.|journal=Journal of Nuclear Medicine |date=April 1984|volume=25|issue=4|pages=499–502|pmid=6100549|url=http://jnm.snmjournals.org/content/25/4/499.full.pdf|access-date=11 May 2012}}

{{Reflist}}

Category:Radiopharmaceuticals

Category:Radioactivity

Category:Technetium-99m

Category:Medical physics