The isotope revolution that can change imaging and therapy Mikael Jensen Professor of Applied Nuclear Physics The Hevesy Laboratory DTU Nutech, Technical University of Denmark George Hevesy
5.5 MeV protons 1938
I must confess that one reason we have undertaken this biological work is that we thereby have been able to get financial support for all of the work in the laboratory. As you know, it is much easier to get funds for medical research. Ernest Orlando Lawrence to Niels Bohr, 1935 Why should you trust a NUCLEAR PHYSICIST trying to change your mind on MEDICAL isotopes? There are no NEW isotopes, really?
Reason to listen: I am one of yours.made my first radiopharmaceutical 1975.. QP for 15 years..
Another reason to listen: Nuclear Medicine has developed greatly because of a push of technology from basic science and National Laboratories. Sadly, not often a pull from the medical side Radium and radon needles The cyclotrons The Manhattan programme Research reactors The Tc-99m generators F-18 and FDG The PET camera Sr-82 and Ge-68 from DOE facilities.. 5
6
PET-CT F-18 FDG T½ =110 min
Nuclear medicine can not work without isotopes. But what isotopes? Reasons to rethink the isotope supply : 1. The research reactor and Mo-99 situation 2. The development of PET-CT 3. The introduction of point-of demand cyclotrons 4. More NM procedures will be needed 5. Present supply chain can not meet global growth give me chance to elaborate before you throw the tomatoes 8
The Moly situation: 9
The Moly situation: 1957 1961 All Mo-99 made in Research Reactors 1961 1964 1957 Build and operated by public money 10
We know how to make new reactors, and we know how to make Mo-99 from LEU! But who s going to pay for the next generation of reactors and separation facilities? What s the price and construction time for a new set of research reactors? What s the price of waste management and facility decommissioning? it is not economically sustainable. 11
Not many reactors are needed. but there will be a reactor deficit unless policies and economics changes Bye, bye cheap neutrons and plentiful fission products 12
Do not panic OECD-NEA, August 2015 13
Do not panic. 14 But perhaps this IS panic?
Cyclotron Tc-99m is possible But it needs re-licensing, new dosimetry, New logistics, and... more money! 15
What s so good or special about Technetium? 16
The development in SPECT-CT and PET-CT The hardware in a BGO based low end PET system is not necessarily more expensive than a SPECT-CT system Tc-99m, I-123, In-111 F-18, Ga-68, Rb-82, C-11 17
Dosimetry!!? PET is always worse? Ga-68 versus Tc99m? A factor of 6 down in PHYSICAL T½ A factor of 10 up in deposited energy But we need less activity injected? 18 Lets go home and ask Olinda about the dose
What would it take to make Ga-68 labelled aggregated human albumin?? Would you see more in the picture? Would you need more examples? You will never get it approved! 19
Ga-68? From where? Ge-68 not easy to make. Very limited world wide supply 20 Obninsk Los Alamos and a few more
Ge-68 generator shortcomings: Price Limited time Limited number of elusions Eluate work-up often needed still, the generator is a wonderfull workhorse We just need more kit radiopharmaceuticals 21
Any small cyclotron can make you 30 GBq of Ga-68 in 1 hour! The solution targets are being developed just now! Cyclotrons will become Ga-68 generators solid targets are probably better.. 22
And Ga-68 yields itself well to chelation, late state labelling and kit chemistry Any good biovector But our cyclotrons can also do Ti-45 = good positron T½=3 hour workhorse Simple target, but needs new chelators! Ga-68 for the simple physological markers - lung and kidney 23
The table-top cyclotrons - or accelerators Bedside cyclotrons? Point-of-demand cyclotrons Many competing designs for 7-8 MeV protons on target- on its way ABT, GE Gentrace, Oniac.. more to come 24
The PT 600 prototype in place
What can we make with 7.8 MeV?
F-18 Small volume gridded Niobium target 10 um Havar, 7.4 MeV into water Grid of Aluminium Experimental experience 30uA 1.3 ml fill total volume 30 Bar overpressure With Argon At 35 ua on grid+ target: 30 = 9-12 GBq EOB 1 h = 20-23 GBq (n=15) 1 h beam, 25 min Fastlab synthesis = 16 GBq FDG EOS + 10 ^11 neutrons/ sec.. SO IT IS NOT a TABLETOP machine!
C-11 N-14 (p,alpha) C-11 This is where we need 7.8 MeV
N2+1%O2 gridded target C-11 as CO2 Experimental experience 135-150-200 psi 35 ua on target 30 ua into gas 30 minutes 12.2-15.0 GBq EOB(n=10) 60 minutes 22-26 GBq EOB (n=1) Specific activity measured by CO2+ Methane total in gas target empty : 4-20 Ci/umol C (150-740 GBq/umol) No labelled compounds yet
Now,- if we dream point of demand.. Why not, at last, do Clinical C-11? C-11 acetate C-11 methionine C-11 choline.. Will need better and deeper automation. Will need automatic QC Will ned new regulatory approach 30
Ga-68 Zn-68 electroplated on Silver 120 micrometer thick Run 60 mins at 30 ua 15 GBq Ga-68 @ EOB (n=2) who needs that? Tc99m replaced by Ga-68? The solution target is not useful at 7.8 MeV
The miniature cyclotron is part of a bigger dream The complete point of demand drug delivery system: Remember the shielding when you dream QC Chemistry Dispense Complete Computer Control Quality by design MTBF > 6 months
The integral hot cell Can we place and safely operate chemistry and radiopharmacy in a single confinement, with complete environmental control? In a otherwise non-descript facility? Can we make syntheis+dispensing + qc release completely automatic? Will it be accepted?
And then a word on therapy: I-131, Y-90, Lu-177 are here to stay. They NEED reactors. GOOD reactors But they can be transported on a global scale. For well targeted, internalised Auger electron emitters, a 13-19 MeV cyclotron can make enough activity for therapeutic patient doses: La-135,- existing chemistry ok Er-165,- existing chemistry ok Sb-119 new chemistry needed Ge-71 new chemistry needed 34 Still only a dream.
CONCLUSION: The real revolution: Radioisotopes for radiopharmaceuticals are made by cyclotrons, locally and only on demand. Well suited for global dissemination Preparing nuclear medicine for personalized medicine era ( = more scans!) Better diagnostic quality Industry will make money providing equipment, kits, starting materials. Only a few reactors will be needed The revolution isotopes: F-18 Ga-68 C-11 Ti-45 N-13 NH3? O-15 water What will it take: 35 More, new and better Chemistry Regulatory redefinition
36 Questions?