18 F-labeled rhodamines as potential myocardial perfusion agents: comparison of pharmacokinetic properties of several rhodamines

Abstract

Introduction We recently reported the development of the [18F]fluorodiethylene glycol ester of rhodamine B as a potential positron emission tomography (PET) tracer for myocardial perfusion imaging (MPI). This compound was developed by optimizing the ester moiety on the rhodamine B core, and its pharmacokinetic properties were found to be superior to those of the prototype ethyl ester. The goal of the present study was to optimize the rhodamine core while retaining the fluorodiethyleneglycol ester prosthetic group. Methods A series of different rhodamine cores (rhodamine 6G, rhodamine 101, and tetramethylrhodamine) were labeled with 18F using the corresponding rhodamine lactones as the precursors and [18F]fluorodiethylene glycol ester as the prosthetic group. The compounds were purified by semipreparative HPLC, and their biodistribution was measured in rats. Additionally, the uptake of the compounds was evaluated in isolated rat cardiomyocytes. Results As was the case with the different prosthetic groups, we found that the rhodamine core has a significant effect on the in vitro and in vivo properties of this series of compounds. Of the rhodamines evaluated to date, the pharmacologic properties of the 18F-labeled diethylene glycol ester of rhodamine 6G are superior to those of the 18F-labeled diethylene glycol esters of rhodamine B, rhodamine 101, and tetramethylrhodamine. As with 18F-labeled rhodamine B, [18F]rhodamine 6G was observed to localize in the mitochondria of isolated rat cardiomyocytes. Conclusions Based on these results, the 18F-labeled diethylene glycol ester of rhodamine 6G is the most promising potential PET MPI radiopharmaceutical of those that have been evaluated to date, and we are now preparing to carry out first-in-human clinical studies with this compound.

New chemical and radiochemical routes to [18F]Rho6G-DEG-F, a delocalized lipophilic cation for myocardial perfusion imaging with PET

“…This general approach was first used for the preparation of modified rhodamine esters bearing carboxylic acid and benzyl chloride functionalities for conjugation to peptides, 23 and later for the synthesis of 19 F reference material 19 F-[1][Cl] . 22 Cation [2] was purified on a glass column packed with C 18 sorbent (50:50 MeCN:H 2 O with 0.5% acetic acid), followed by solid-phase extraction from the liquid chromatography (LC) eluent. The final product was determined to be the singly charged tosylate salt [2][OTs] .…”

“…Molar activities were calculated based on a calibration curve prepared from an 19 F standard 22 ( [2][OTs] = 3–9 GBq/μmol; [2][HCOO][OTs] = 7–35 GBq/μmol). These molar activity values are similar to those typically observed for manual 18 F syntheses carried out using small quantities (370–740 MBq) of [ 18 F]fluoride ion obtained from transfer line flushes after clinical production of other radiotracers.…”

“…21 Building on our earlier work with rhodamine B, we later compared the pharmacological properties of a series 2-(2-[ 18 F]fluoroethoxy)ethyl ester derivatives bearing different rhodamine cores. 22 These 18 F-labeled rhodamine esters were prepared by condensing a rhodamine in the lactone form with the requisite 18 F/tosyl-bearing bifunctional prosthetic molecule. An example synthesis is shown in Scheme 1.…”

“…On the basis of these experiments, rhodamine 6G 2-(2-[ 18 F]fluoroethoxy)ethyl ester, chloride salt ([ 18 F]Rho6G-DEG-F, 18 F-[1][Cl] ; Scheme 1) was identified as the most promising MPI candidate, exhibiting effective localization in isolated rat cardiomyocytes (4.6%±0.7% ID/g at 1 min), rapid and sustained uptake into rat hearts (1.3%±0.3% ID/g at 60 min), and excellent contrast between the heart and nearby liver tissues. 22 This two-step method for the preparation of 18 F- [1][Cl] is not, however, optimal for routine production using automated synthesis modules primarily because the lactone precursor is sparingly soluble in many organic solvents, including MeCN. An additional limitation is that it requires two radiochemical steps.…”

Summed rest score in gated myocardial perfusion imaging is a good predicator for treatment-related cardiotoxicity after anthracycline chemotherapy in diffuse large B-cell lymphoma patients

“…Therefore, G-MPI can show abnormal local myocardial perfusion, which can be used for early noninvasive evaluation of abnormal changes in mitochondrial function of cardiomyocytes [43][44][45].…”