RT Journal Article SR Electronic T1 First Clinicopathologic Evidence of a Non–PSMA-Related Uptake Mechanism for 68Ga-PSMA-11 in Salivary Glands JF Journal of Nuclear Medicine JO J Nucl Med FD Society of Nuclear Medicine SP 1270 OP 1276 DO 10.2967/jnumed.118.222307 VO 60 IS 9 A1 Niels J. Rupp A1 Christoph A. Umbricht A1 Daniele A. Pizzuto A1 Daniela Lenggenhager A1 Antonia Töpfer A1 Julian Müller A1 Urs J. Muehlematter A1 Daniela A. Ferraro A1 Michael Messerli A1 Grégoire B. Morand A1 Gerhard F. Huber A1 Daniel Eberli A1 Roger Schibli A1 Cristina Müller A1 Irene A. Burger YR 2019 UL http://jnm.snmjournals.org/content/60/9/1270.abstract AB The intense accumulation of prostate-specific membrane antigen (PSMA) radioligands in salivary glands is still not well understood. It is of concern for therapeutic applications of PSMA radioligands, because therapeutic radiation will damage these glands. A better understanding of the uptake mechanism is, therefore, crucial to find solutions to reduce toxicity. The aim of this study was to investigate whether the accumulation of PSMA-targeting radioligands in submandibular glands (SMGs) can be explained with PSMA expression levels using autoradiography (ARG) and immunohistochemistry (IHC). Methods: All patients gave written informed consent for further utility of the biologic material. The SMG of 9 patients, pancreatic tissue of 4 patients, and prostate cancer (PCA) lesions of 9 patients were analyzed. Tissue specimens were analyzed by means of PSMA-IHC (using an anti–PSMA-antibody and an immunoreactivity score system [IRS]) and ARG using 177Lu-PSMA-617 (with quantification of the relative signal intensity compared with a PSMA-positive standard). The SUVmax in salivary glands, pancreas, and PCA tissues were quantified in 60 clinical 68Ga-PSMA-11 PET scans for recurrent disease as well as the 9 primary tumors selected for ARG and IHC. Results: PCA tissue samples revealed a wide range of PSMA staining intensity on IHC (IRS = 70–300) as well as in ARG (1.3%–22% of standard). This variability on PCA tissue could also be observed in 68Ga-PSMA-11 PET (SUVmax, 4.4–16) with a significant correlation between ARG and SUVmax (P < 0.001, R2 = 0.897). On IHC, ARG, and 68Ga-PSMA-11 PET, the pancreatic tissue was negative (IRS = 0, ARG = 0.1% ± 0.05%, SUVmax of 3.1 ± 1.1). The SMG tissue displayed only focal expression of PSMA limited to the intercalated ducts on IHC (IRS = 10–15) and a minimal signal on ARG (1.3% ± 0.9%). In contrast, all SMG showed a high 68Ga-PSMA-11 accumulation on PET scans (SUVmax 23.5 ± 5.2). Conclusion: Our results indicate that the high accumulation of PSMA radioligands in salivary glands does not correspond to high PSMA expression levels determined using ARG and IHC. These findings provide evidence, that the significant accumulation of PSMA radioligands in SMG is not primarily a result of PSMA-mediated uptake.