Radiopharmaceutical for low-cost and high-sensitivity diagnosis of early-stage dementia and tissue viability in acute stroke.
Challenge
Neuronal activity critically depends on transmembrane potassium (K+) fluxes and on the maintenance of intra- to extracelluar K+-gradients. K+-fluxes increase with increasing activity. K+-equilibrium potentials – and intracellular K+-contents - change with changes in membrane potential that can occur upon long-term up- or down-regulations of electrical activity. Breakdown of K+-gradients indicates failure of energy supply. Conversely, maintenance of K+-gradients is a viability marker. In addition, clearance of K+ out of the brain is related to the integrity of the blood-brain barrier (BBB).
Brain K+-metabolism thus is of fundamental clinical relevance. In particular, imaging the spatial patterns of chronically up- or down-regulated neuronal activity and of transport rates across the BBB in early stages of dementia as well as tissue viability in acute stroke are of substantial interest in neurology.
Attempts have been made to image cerebral K+-content using magnetic resonance imaging of 42K, but the technique is insensitive and not able to image the dynamics of K+-uptake and -excretion. In principle, K+-turnover can be imaged using the well-established K+-probe 201Thallium (201Tl+, or simply 201Tl), a radionuclide suitable for detection with single-photon emission computed tomography (SPECT). SPECT is a relatively inexpensive widely available clinical imaging modality that, with newest generation scanners, can provide the same spatial resolution as positron emission tomography (PET). 201Tl-SPECT is in use since many decades for imaging myocardial ischemia and infarction. The transport of 201Tl through the BBB, however, is slow and only minute amounts of 201Tl can be found in the brain in the first hours after intravenous injection of 201Tl chloride. Without catalyzing the transport of 201Tl through the BBB, the radionuclide cannot be used for imaging brain K+-metabolism.
Distribution of Thallium after injection in rat brain at 15 min (A,B) and 7 days (C,D) after introduction of cerebral ischemia. The asterisk in B indicates the center of the ischemia.
Technology
We have shown that the lipophilic diethyldithiocarbamate anion (termed DDC- or DEDTC-) catalyzes the transport of 201Tl+ through the BBB. 201Tl+ and DDC- reversibly form the electroneutral lipophilic chelate complex 201TlDDC that passes the BBB. 201Tl-content in the brain shortly after intravenous 201TlDDC injection is about 100 times higher than after 201Tl chloride injection.
After passage through the BBB, 201Tl is released from the compound. Neurons and astrocytes take up the Tl+-ion and the kinetics of Tl+-efflux from the brain mimic the kinetics of the slow K+-efflux. The relatively long half-life of 201Tl of 72 hours makes it possible to monitor uptake, redistribution and clearance from the brain over at least 24h.
We have shown, in mouse models of dementia, that after intravenous 201TlDDC injection both initial brain uptake patterns of 201Tl and the kinetics of 201Tl-loss differ from those in wild-type mice, and that monitoring the 201Tl-loss kinetics provides additional information not contained in the early images. Both, 201Tl-uptake and –loss, were also severely altered in rodent stroke models, and our data show that 201Tl-retention after 201TlDDC injection can serve as a viability-marker.
Synthesis of 201TlDDC is a quick one-step procedure that works by just mixing 201Tl+ with sodium diethyldithiocarbamate (NaDDC). DDC- is an inexpensive compound. It is well-known in medicine as it is generated in vivo from Disulfiram (Antabus©), which is prescribed in doses far exceeding those needed for SPECT-imaging.
201TlDDC is a radiopharmaceutical for SPECT-imaging of brain K+-metabolism easily synthesized from two well-characterized components. Compared to SPECT-imaging of cerebral blood flow and PET-imaging of glucose metabolism it offers an additional dimension by imaging not only the uptake but also the kinetics of redistribution and clearance from the brain.
Commercial Opportunity
In-licensing (exclusive or non-exclusive) is possible.
Development Status
Pre-clinical studies completed (see Reference Literature), ready to submit for clinical trial.
Patent Situation
Patents have been granted in Europe, US and Korea with priority of 2005.
Further Reading
Goldschmidt J et al. (2010) High-resolution mapping of neuronal activity using the lipophilic thallium chelate complex TlDDC: protocol and validation of the method. NeuroImage 49:303-15.
Wanger T et al. (2012) The use of thallium diethyldithiocarbamate for mapping CNS potassium metabolism and neuronal activity: Tl+ -redistribution, Tl+ -kinetics and Tl+ -equilibrium distribution. J Neurochem 122:106-14.
Lison H et al- (2014) Disrupted cross-laminar cortical processing in β amyloid pathology precedes cell death. Neurobiol Dis 63:62-73.
Stöber F et al. (2014) Single-cell resolution mapping of neuronal damage in acute focal cerebral ischemia using thallium autometallography. J Cereb Blood Flow Metab 34:144-152.
Goldschmidt J et al. (2017) BMBF-Vorhaben „Validierung des Innovationspotenzials wissenschaftlicher Forschung – VIP“ – 201TlDDC-SPECT zur Frühdiagnostik dementieller Erkrankungen, Abschlussbericht. Technische Informationsbibliothek 2017 (BMBF funded project, validation of the innovative potential of scientific research – 201TlDDC-SPECT for early diagnosis of dementias, final report).
Stöber et al. in preparation: SPECT-imaging of K+-metabolism in acute cerebral ischemia using 201TlDDC, a lipophilic chelate complex of the K+-probe 201Tl+.
Institute of Origin
