The Impact of Monosodium Glutamate on ⁶⁸Ga-PSMA-11 Biodistribution in Men with Prostate Cancer: A Prospective Randomized, Controlled Imaging Study

Abstract

Background:The prostate-specific membrane antigen (PSMA) has been targeted for PET imaging and radioligand therapy (RLT) in patients with prostate cancer. Xerostomia is a common side effect of RLT due to high salivary gland uptake of PSMA-radioligands.Here we aimed to determine the impact of monosodium glutamate (MSG) administration on PSMA-radioligand biodistribution within healthy organs and tumor lesions by using 68 Ga-PSMA-11 PET imaging.Methods: 16 men with prostate cancer were randomized (1:1) into oral ingestion and oral topical application ('swishing') arms. Each subject underwent two 68 Ga-PSMA-11 PET/CT scans within 14 days under baseline and MSG conditions. Salivary glands and wholebody tumor lesions were segmented using qPSMA software. We quantified tracer uptake via mean and maximum standardized uptake values (SUVmean and SUVmax) and compared parameters within each patient.Results: For the oral ingestion arm, salivary gland SUVmean/max decreased on average from Control to MSG scan by 45±15% (p=0.004) and 53±11% (p<0.001), respectively.Tumor lesions SUVmean/ max also decreased by 38% (IQR -67%, -33%) and -52% (IQR -70%, -49%), respectively (p=0.018). Swishing had no significant effect on 68 Ga-PSMA-11 accumulation in normal organs or tumor lesions. Conclusion:Oral ingestion but not topical application of MSG reduced 68 Ga-PSMA-11 uptake in salivary glands. Tumor uptake also declined, therefore, the clinical application of MSG is unlikely to be useful in the framework of RLT.

Characterization of Non-Specific Uptake and Retention Mechanisms of [177Lu]Lu-PSMA-617 in the Salivary Glands

“…However, we also observed a decreased binding of [ 177 Lu]Lu-PSMA-617 when treated with higher MSG concentrations, suggesting that MSG might be able to reduce tumor uptake when dosing is too high. This data is in accordance with published reports, where decreased uptake was observed in patients treated with [ 68 Ga]Ga-PSMA-11 after the oral administration of MSG [ 21 ].…”

What a difference a methylene makes: replacing Glu with Asp or Aad in the Lys-urea-Glu pharmacophore of PSMA-targeting radioligands to reduce kidney and salivary gland uptake

“…The reason for replacing Glu in the pharmacophore to reduce kidney and salivary gland uptake of PSMA-targeting radioligands was because of the report showing the use of monosodium glutamate to reduce uptake of [ 68 Ga]Ga-PSMA-11 in kidneys and salivary glands but not LNCaP tumor xenografts 15 . However, it should be noted that recent clinical studies showed that the ingestion of 12.7 g and 18.9 g of monosodium glutamate reduced the uptake of [ 18 F]DCFPyL and [ 68 Ga]Ga-PSMA-11, respectively, in not only kidneys and salivary glands but also in prostate cancer lesions 30 - 31 . This suggests that there might be species differences for the distribution of PSMA and off-targets in prostate tumors, kidneys and salivary glands.…”

Global experience with PSMA-based alpha therapy in prostate cancer

“…The effectiveness of this intervention is still under debate [97,98]. Competitive inhibition for binding at PSMA receptor expressed in normal organs has been attempted with cold PSMA or PSMA congeners such as monosodium glutamate as another way to reduce off-target PSMA radioligand uptake in the salivary glands [99][100][101][102][103]. While this competitive inhibition may successfully reduce off-target PSMA radioligand in normal organs such as the salivary gland, a reduction in tumor uptake is possible [102].…”