Abstract
Introduction In vivo pH imaging has been a field of interest for molecular imaging for many years. This is especially important for determining tumor acidity, an important driving force of tumor invasion and metastasis formation, but also in the process of apoptosis.Methods2-(4-[123I]iodophenethyl)-2-methylmalonic acid (IPMM), 2-(4-[123I]iodophenethyl)-malonic acid (IPM), 2-(4-[123I]iodobenzyl)-malonic acid (IBMM) and 4-[123I]iodophthalic acid (IP) were radiolabeled via the Cu+ isotopic nucleophilic exchange method. All tracers were tested in vitro in buffer systems to assess pH driven cell uptake. In vivo biodistribution of [123I]IPMM and [123I]IPM was determined in healthy mice and the pH targeting efficacy in vivo of [123I]IPM was evaluated in an anti-Fas monoclonal antibody (mAb) apoptosis model. In addition a mouse RIF-1 tumor model was explored in which tumor pH was decreased from 7.0 to 6.5 by means of induction of hyperglycemia in combination with administration of meta-iodobenzylguanidine.ResultsRadiosynthesis resulted in 15–20% for iodo-bromo exchange and 50–60% yield for iodo-iodo exchange while in vitro experiments showed a pH-sensitive uptake for all tracers. Shelf-life stability and in vivo stability was excellent for all tracers. [123I]IPMM and [123I]IPM showed a moderately fast predominantly biliary clearance while a high retention was observed in blood. The biodistribution profile of [123I]IPM was found to be most favorable in view of pH-specific imaging. [123I]IPM showed a clear pH-related uptake pattern in the RIF-1 tumor model.ConclusionIodine-123 labeled malonic acid derivates such as [123I]IPM show a clearly pH dependent uptake in tumor cells both in vitro and in vivo which allows to visualize regional acidosis. However, these compounds are not suitable for detection of apoptosis due to a poor acidosis effect.
Highlights
In vivo pH imaging has been a field of interest for molecular imaging for many years
Identification of the synthesized products was achieved with time-of-flight mass spectrometry (TOF-MS) (LCT, Micromass), with an orthogonal electrospray ionization (ESI) interface
HPLC purification allowed for the collection of pure 123I-labeled IBMM, IP, IPM and IPMM in a volume of maximum 3 ml (1 min collection)
Summary
In vivo pH imaging has been a field of interest for molecular imaging for many years. Due to the poor perfusion, this increased extracellular acidity is not washed away by the blood flow, and an intratumoral acidic pH is created This process was first described by Warburg and is currently known as ‘the Warburg effect’ [5]. Basic chemotherapeutic drugs, such as anthracyclines, anthraquinones and vinca alkaloids, are assumed to accumulate in the (intracellular) acidic sections of the cancer cell The uptake of these compounds can be diminished if the extracellular pH (pHe) is decreased. Jahde et al showed in 1992 that a combination of hyperglycemia and a single administration of meta-iodobenzylguanidine (MIBG) significantly decreased intratumoral pHe from 6.9 to 6.2 [12] This drastic acidification had no significant impact on cell survival
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