Figure 1. Instrumented generator for clinical production of the positron emitting radioisotope 62Cu
Concept
Currently, clinical PET depends almost exclusively upon the single radiopharmaceutical, 18F-FDG. The half life of 18F, 109.8 min, dictates the need for cyclotron equipped radiopharmacies relatively close to hospital locations. There are many radiopharmaceuticals based upon 18F in the pipeline, however the requirement of GMP production at the 50 or more individual distribution centers causes high cost and lengthy development time line. PTI has developed an instrumented user friendly microgenerator based on the radionuclide pair 62Zn/62Cu. This system supports multiple compound formulations (based upon the bisThiosemicarbazone (BTS) family) through the use of ligand kits. Three of such kits are currently in the FDA pipeline supported by PTI sponsored IND’s.
Fig 2. Microgenerator and Kits.
The microgenerator is compact, light-weight and readily distributable throughout the continental US by overnight courier service. The half-life of 62Cu of 9.7 minutes is nearly ideal for clinical imaging affording very high injected dose levels along the clinic use day. For example, Figure 3 shows the extractable activity from a typical microgenerator loaded with 50 mCi of 62Zn at 8:00am Clinic Day; with waiting times ranging from 10-30 minutes, the user can easily obtain ~42mCi of 62Cu in the early hours down to ~22mCi of 62Cu at 5:00 pm. This facilitates use of multiple serial studies with either the same or different kit formulations. For example rest/stress myocardial studies or the application of two or more tracers for tumor assessment. Such serial studies can be accomplished in similar scanning times to those currently employed for single PET or SPECT studies.
The generator compares economically favorable with 18F because a small batch of 62Zn can be likened to a batch of 18F-FDG. The 18F-FDG is divided into individual doses similar in number to the output of a single Zn/Cu generator. The 18F-FDG must be produced locally, however because of the much shorter half life of 18F. That means that a large number of GMP facilities and cyclotrons must be employed whereas national distribution of Zn/Cu generator can be done from one or a small number of centralized facilities.
The BTS family of compounds provides multiple small molecular entities with high potential for the important applications of perfusion and hypoxia imaging. An important feature of the 62Zn/62Cu generator is the exceptionally high specific activity of the radiocopper of 1000 mCi/μg of cold copper with a typical 30 mCi clinic elution dose. Because of this, 62Cu based biomolecular agents can target bioprocesses at the nanomolar level allowing probing orders of magnitude below levels currently available with agents such as 64Cu(link to more technical description of specific activity and ramifications).
Figure 3: Graph showing regrowth of available 62Cu over an 8 hour day clinic day. A total of 22 elutions with 10, 20 and 30 minute regrowth time are shown.
Features
The generator module combines a tungsten shielded column, liquid delivery system, and a needle output port into a single compact cylindrical stainless steel housing. The ruggedness of the module is compatible with safe shipment. On-demand daily delivery of the generator creates flexibility and economic advantages by allowing order of the generator only on certain days of the week tailored to clinical schedule. With elution and instant synthesis of PET agents completed in 30 seconds, the operation of the generator is simple and convenient, requiring only minimal training for clinic personnel. Each elution results in a single injectable dose consisting of 15 - 50 mCi 62Cu in 4 mL sterile, pyrogen free, acetate buffered, isotonic solution. The short half-life 62Cu (T-1/2 = 9.7 min) allows clinical injections to be performed at intervals as frequent as every 15 min, and the low patient radiation dose permits multiple studies in one clinic visit.
Figure 4: Built in electronics
A multi-parametric sensor board is under development and will soon be installed in the generator providing on-site elution analysis and quality control. This system will eventually be combined with a controller at the clinic site for totally automated delivery of desired dose levels. With its built-in analogue electronics along with a data acquisition card and a PC, permanent recorded digital-monitoring of the radioisotopes production will be provided at the clinical site, providing real-time analysis and quality control of each elution. Through a NI LabView 8.2® panel, the user instantly obtains the results of the analyses, as each elution is completed.
Figure 5: Real time Elution Profile
Regulatory Status
•62Cu -PTSM has FDA clearance for investigational studies since December 21, 1995
• 62Cu-ATSM received FDA clearance to begin clinical investigational studies on February 7, 2007
• 62Cu -ETS received FDA clearance to begin clinical investigational studies on May 30, 2006
• First generation 62Zn/62Cu generator system received FDA clearance to begin clinical investigational studies on June 13, 2002. 62Cu -ETS – Phase I final report submitted on 09/18/07
• 62Cu -ETS - received FDA clearance to begin Phase II clinical investigational studies – 02/05/08
• 62Cu -ATSM – Phase I studies completed on 03/2008, and a final report in preparation
This technology has been funded by the following grants-
NIH under the project name “Improved Production of 62Zn for PET Imaging with 62Cu" – HHSN261-200622026C.
NIH under the project name "Instant Kit Synthesis of 62Cu Radiopharmaceuticals" - CA110154.
NIH under the project name "Regional Renal Perfusion Quantification with 62Cu PET" - DK58466
References:
JL Lacy, L Guerrero, R Chiu, L Sun, L Hall, CK Stone. “PET Imaging with 62Cu-ETS in a Human Clinical Trial at the University of Wisconsin – Madison.” IEEE Nuclear Science Symposium and Medical Imaging Conference Record, Vol. 5, Oct. 2007, p. 4027-4030. (Download)*
Haynes, N. G. et al. “Performance of a 62Zn/62Cu Generator in Clinical Trials of PET Perfusion Agent 62Cu-PTSM” J. Nucl. Med. 2000. 41(2), 309-14. (Download)**
Zimmerman, B. E.;Cessna, J.T. “The standardization of 62Cu and experimental determinations of dose calibrator settings for generator-produced 62CuPTSM.” Applied Radiation Isotopes, 1999, 51, 515-26. (doi:10.1016/S0969-8043(99)00078-0)
Tadamura, E. et al. “Generator-Produced 62Cu-PTSM as a Myocardial PET Perfusion Tracer Compared with Nitrogen-13-Ammonia.” 1996 J. Nucl. Med., 37(5), 729-735. (Pubmed)
Okazawa, H. et al. “Clinical Application and Quantitative Evaluation of Generator-Produced 62Cu-PTSM as a Brain Perfusion Tracer for PET” J. Nucl. Med. 1994, 35(12), 1910-15. (Pubmed)
Mathias, C. J.. et al. “Evaluation of a Potential Generator-Produced PET Tracer for Cerebral Perfusion Imaging: Single-Pass Cerebral Extraction Measurements and Imaging with Radiolabeled Cu-PTSM” J. Nucl. Med. 1990, 31(3), 351-9. (JNM Link)
Robinson, G, D, Jr; Zielinsky, F.W.; Lee, A, W. “The Zinc-62/Copper-62 Generator: A Convenient Source of 62Cu for Radiopharmaceuticals” Int. J. App. Radiation and Isotopes 1980, 31, 111-6. (PubMed)
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** Reprinted by permission of the Society of Nuclear Medicine
