Cerenkov Radiation Energy Transfer (CRET) Imaging: A Novel Method for Optical Imaging of PET Isotopes in Biological Systems

Positron emission tomography (PET) allows sensitive, non-invasive analysis of the distribution of radiopharmaceutical tracers labeled with positron (β(+))-emitting radionuclides in small animals and humans. Upon β(+) decay, the initial velocity of high-energy β(+) particles can momentarily exceed the speed of light in tissue, producing Cerenkov radiation that is detectable by optical imaging, but is highly absorbed in living organisms.To improve optical imaging of Cerenkov radiation in biological systems, we demonstrate that Cerenkov radiation from decay of the PET isotopes (64)Cu and (18)F can be spectrally coupled by energy transfer to high Stokes-shift quantum nanoparticles (Qtracker705) to produce highly red-shifted photonic emissions. Efficient energy transfer was not detected with (99m)Tc, a predominantly γ-emitting isotope. Similar to bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET), herein we define the Cerenkov radiation energy transfer (CRET) ratio as the normalized quotient of light detected within a spectral window centered on the fluorophore emission divided by light detected within a spectral window of the Cerenkov radiation emission to quantify imaging signals. Optical images of solutions containing Qtracker705 nanoparticles and [(18)F]FDG showed CRET ratios in vitro as high as 8.8±1.1, while images of mice with subcutaneous pseudotumors impregnated with Qtracker705 following intravenous injection of [(18)F]FDG showed CRET ratios in vivo as high as 3.5±0.3.Quantitative CRET imaging may afford a variety of novel optical imaging applications and activation strategies for PET radiopharmaceuticals and other isotopes in biomaterials, tissues and live animals

Quantitative Modeling of Cerenkov Light Production Efficiency from Medical Radionuclides

There has been recent and growing interest in applying Cerenkov radiation (CR) for biological applications. Knowledge of the production efficiency and other characteristics of the CR produced by various radionuclides would help in accessing the feasibility of proposed applications and guide the choice of radionuclides. To generate this information we developed models of CR production efficiency based on the Frank-Tamm equation and models of CR distribution based on Monte-Carlo simulations of photon and β particle transport. All models were validated against direct measurements using multiple radionuclides and then applied to a number of radionuclides commonly used in biomedical applications. We show that two radionuclides, Ac-225 and In-111, which have been reported to produce CR in water, do not in fact produce CR directly. We also propose a simple means of using this information to calibrate high sensitivity luminescence imaging systems and show evidence suggesting that this calibration may be more accurate than methods in routine current use

Three-dimensional Noninvasive Monitoring Iodine-131 Uptake in the Thyroid Using a Modified Cerenkov Luminescence Tomography Approach

BACKGROUND: Cerenkov luminescence tomography (CLT) provides the three-dimensional (3D) radiopharmaceutical biodistribution in small living animals, which is vital to biomedical imaging. However, existing single-spectral and multispectral methods are not very efficient and effective at reconstructing the distribution of the radionuclide tracer. In this paper, we present a semi-quantitative Cerenkov radiation spectral characteristic-based source reconstruction method named the hybrid spectral CLT, to efficiently reconstruct the radionuclide tracer with both encouraging reconstruction results and less acquisition and image reconstruction time. METHODOLOGY/PRINCIPAL FINDINGS: We constructed the implantation mouse model implanted with a 400 µCi Na(131)I radioactive source and the physiological mouse model received an intravenous tail injection of 400 µCi radiopharmaceutical Iodine-131 (I-131) to validate the performance of the hybrid spectral CLT and compared the reconstruction results, acquisition, and image reconstruction time with that of single-spectral and multispectral CLT. Furthermore, we performed 3D noninvasive monitoring of I-131 uptake in the thyroid and quantified I-131 uptake in vivo using hybrid spectral CLT. Results showed that the reconstruction based on the hybrid spectral CLT was more accurate in localization and quantification than using single-spectral CLT, and was more efficient in the in vivo experiment compared with multispectral CLT. Additionally, 3D visualization of longitudinal observations suggested that the reconstructed energy of I-131 uptake in the thyroid increased with acquisition time and there was a robust correlation between the reconstructed energy versus the gamma ray counts of I-131 (r(2) = 0.8240). The ex vivo biodistribution experiment further confirmed the I-131 uptake in the thyroid for hybrid spectral CLT. CONCLUSIONS/SIGNIFICANCE: Results indicated that hybrid spectral CLT could be potentially used for thyroid imaging to evaluate its function and monitor its treatment for thyroid cancer

Drosophila Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu