Towards longitudinal mapping of extracellular pH in gliomas.

Biosensor imaging of redundant deviation in shifts (BIRDS), an ultrafast chemical shift imaging technique, requires infusion of paramagnetic probes such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis methylene phosphonate (DOTP(8-) ) complexed with thulium (Tm(3+) ) ion (i.e. TmDOTP(5-) ), where the pH-sensitive resonances of hyperfine-shifted non-exchangeable protons contained within the paramagnetic probe are detected. While imaging extracellular pH (pHe ) with BIRDS meets an important cancer research need by mapping the intratumoral-peritumoral pHe gradient, the surgical intervention used to raise the probe's plasma concentration limits longitudinal scans on the same subject. Here we describe using probenecid (i.e. an organic anion transporter inhibitor) to temporarily restrict renal clearance of TmDOTP(5-) , thereby facilitating molecular imaging by BIRDS without surgical intervention. Co-infusion of probenecid with TmDOTP(5-) increased the probe's distribution into various organs, including the brain, compared with infusing TmDOTP(5-) alone. In vivo BIRDS data using the probenecid-TmDOTP(5-) co-infusion method in rats bearing RG2, 9 L, and U87 brain tumors showed intratumoral-peritumoral pHe gradients that were unaffected by the probe dose. This co-infusion method can be used for pHe mapping with BIRDS in preclinical models for tumor characterization and therapeutic monitoring, given the possibility of repeated scans with BIRDS (e.g. over days and even weeks) in the same subject. The longitudinal pHe readout by the probenecid-TmDOTP(5-) co-infusion method for BIRDS adds translational value in tumor assessment and treatment.