Cerenkov-Specific Contrast Agents for Detection of pH In Vivo

Journal of Nuclear Medicine

Alejandro D. Arroyo¹  Edward J. Delikatny¹  Eric Blankemeyer¹  Joel S. Karp¹  Anatoliy V. Popov¹  Julie Czupryna¹  Alexander V. Kachur¹ 

[1] Small Animal Imaging Facility, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Small Animal Imaging Facility, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Small Animal Imaging Facility, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

关键词: Cerenkov imaging;    ratiometric imaging;    pH measurement;    electrophilic fluorination;    metacresol purple;    phenolphthalein;   

DOI  :  10.2967/jnumed.114.146605

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

We report the design, testing, and in vivo application of pH-sensitive contrast agents designed specifically for Cerenkov imaging. Radioisotopes used for PET emit photons via Cerenkov radiation. The multispectral emission of Cerenkov radiation allows for selective bandwidth quenching, in which a band of photons is quenched by absorption by a functional dye. Under acidic conditions, 18F-labeled derivatives emit the full spectrum of Cerenkov light. Under basic conditions, the dyes change color and a wavelength-dependent quenching of Cerenkov emission is observed. Methods: Mono- and di-18F-labeled derivatives of phenolsulfonphthalein (phenol red) and meta-cresolsulfonphthalein (cresol purple) were synthesized by electrophilic fluorination. Cerenkov emission was measured at different wavelengths as a function of pH in vitro. Intramolecular response was measured in fluorinated probes and intermolecular quenching by mixing phenolphthalein with 18F-FDG. Monofluorocresol purple (MFCP) was tested in mice treated with acetazolamide to cause urinary alkalinization, and Cerenkov images were compared with PET images. Results: Fluorinated pH indicators were produced with radiochemical yields of 4%–11% at greater than 90% purity. Selective Cerenkov quenching was observed intramolecularly with difluorophenol red or monofluorocresol purple and intermolecularly in phenolphthalein 18F-FDG mixtures. The probes were selectively quenched in the bandwidth closest to the indicator’s absorption maximum (λmax) at pHs above the indicator pKa (the negative logarithm of the acid dissociation constant). Addition of acid or base to the probes resulted in reversible switching from unquenched to quenched emission. In vivo, the bladders of acetazolamide-treated mice exhibited a wavelength-dependent quenching in Cerenkov emission, with the greatest reduction occurring near the λmax. Ratiometric imaging at 2 wavelengths showed significant decreases in Cerenkov emission at basic pH and allowed the estimation of absolute pH in vivo. Conclusion: We have created contrast agents that selectively quench photons emitted during Cerenkov radiation within a given bandwidth. In the presence of a functional dye, such as a pH indicator, this selective quenching allows for a functional determination of pH in vitro and in vivo. This method can be used to obtain functional information from radiolabeled probes using multimodal imaging. This approach allows for the imaging of nonfluorescent chromophores and is generalizable to any functional dye that absorbs at suitable wavelengths.

【 授权许可】

Unknown