Evaluation of copper-labeled Cu(II) bis(thiosemicarbazone) complexes as blood flow tracers for positron emission tomography
Abstract
Positron emission tomography (PET) is nuclear medicine imaging technique not widely available for clinical diagnosis due to the expense of producing positron emitting radiolabels. The development of radiotracers labeled with generator-produced positron emitters would facilitate the use of PET by eliminating the need for an in-house cyclotron. Copper-62 is a generator-produced positron emitter potentially useful for labeling PET radiopharmaceuticals. Copper-62 labeled Cu(II) pyruvaldehyde bis(N$\sp4$-methylthiosemicarbazone), Cu(PTSM), is a proposed PET perfusion tracer of the brain, heart, and kidneys. After intravenous injection in animals, copper-labeled Cu(PTSM) affords high initial uptake followed by prolonged retention of radiocopper in these organs. The radiocopper retention is thought to be a result of reductive decomposition of the copper-labeled copper(II) complex by intracellular glutathione, GSH. To validate copper-62 labeled Cu(PTSM) as a myocardial and renal perfusion tracer, the regional radiocopper level afforded by intravenous copper-67 labeled Cu(PTSM) was compared to the absolute blood flow measured with labeled microspheres in normal dog kidneys and surgically infarcted myocardia. In the heart and randomly sectioned kidneys, an excellent linear correlation resulted. In kidneys dissected to separate anatomical regions, radiocopper levels increased monotonically with increasing blood flows for individual dogs, but a linear correlation was observed when data from 12 animals was combined. Should the distribution of Cu(PTSM) vary with naturally occurring GSH fluctuations, the clinical utility of this radiotracer would be limited. Therefore, to validate further copper-62 labeled Cu(PTSM), the biodistribution of copper-67 labeled Cu(PTSM) was determined in GSH-depleted rats. Relatively large GSH reductions in the experimental animals caused only slight changes in the distribution of Cu(PTSM). To define further the physicochemical and structural requirements of metal-labeled perfusion tracers, a series of 23 copper-67 labeled Cu(II) bis(thiosemicarbazone) diketone and dialdehyde complexes were synthesized, their octanol/water partition coefficients measured, and their biodistributions determine in rats. Of the compounds studied, copper-67 labeled Cu(1,4-CyTSM) and Cu(1,4-BuTSM) produced the highest initial brain uptake, similar to Cu(PTSM), and prolonged retention of radiocopper.
Degree
Ph.D.
Advisors
Green, Purdue University.
Subject Area
Pharmaceuticals|Pharmacology|Biomedical research
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