Sublingual Atropine Administration as a Tool to Decrease Salivary Glands' PSMA-Ligand Uptake: A Preclinical Proof of Concept Study Using [68Ga]Ga-PSMA-11

Abstract

Prostate Specific Membrane Antigen (PSMA)-directed radionuclide therapy has gained an important role in the management of advanced castration-resistant prostate cancer. Although extremely promising, the prolongation in survival and amelioration of disease-related symptoms must be balanced against the direct toxicities of the treatment. Xerostomia is amongst the most common and debilitating of these, particularly when using an alpha emitter. It is therefore of main importance to develop new preventive strategies. This preclinical study has evaluated the effect of α-adrenergic and anticholinergic drugs on [99mTc]TcO4− Single Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) and [68Ga]Ga-PSMA-11 Positron Emission Tomography (PET/CT). Methods: The effects of phenylephrine, scopolamine, atropine, and ipratropium on salivary glands uptake were evaluated in non-tumor-bearing mice by [99mTc]TcO4− microSPECT/CT. The most efficient identified strategy was evaluated in non-tumor-bearing and xenografted mice by [68Ga]Ga-PSMA-11 PET/CT. Results: Scopolamine and atropine showed a significant decrease in the parotid glands’ uptake on SPECT/CT whereas phenylephrine and ipratropium failed. Atropine premedication (sublingual route), which was the most effective strategy, also showed a drastic decrease of [68Ga]Ga-PSMA-11 salivary glands’ uptake in both non-tumor-bearing mice (−51.6% for the parotids, p < 0.0001) and human prostate adenocarcinoma xenografted mice (−26.8% for the parotids, p < 0.0001). Conclusion: Premedication with a local administration of atropine could represent a simple, safe, and efficient approach for reducing salivary glands’ uptake.

Keywords: PSMA; atropine; prostate-specific membrane antigen; salivary glands.

Figure 1

Representative MIP images and normalized quantification of microSPECT/CT biodistribution of [^99mTc]TcO₄⁻ in parotid glands at 45 min after injection in non-tumor-bearing mice premedicated with phenylephrine (Phe) 5 mg kg⁻¹ ip (A,F), scopolamine (Sco) ip 5 mg kg⁻¹ (B,G), atropine (Atro) ip 15 mg kg⁻¹ (C,H), atropine sl 15 mg kg⁻¹ (D,I), or ipratropium sl 4 mg kg⁻¹ (E,J). Red points represent the mean ± SEM; black points represent the sample dispersion. (Statistical test has been performing using paired t-test.

Figure 2

(A) Representative MIP images of microPET/CT biodistribution and the quantification of [⁶⁸Ga]Ga-PSMA-11 in the parotids and submandibular glands in non-tumor-bearing mice premedicated with atropine sublingually, at 15 mg kg⁻¹. The parotid glands are encircled in white and the submandibular glands are in orange. (B) Normalized quantification of [⁶⁸Ga]Ga-PSMA-11 in the parotids and submandibular glands in non-tumor-bearing mice. Red points represent the mean ± SEM; black points represent the sample dispersion.

Figure 3

(A) Representative MIP images of microPET/CT biodistribution of [⁶⁸Ga]Ga-PSMA-11 in parotid glands and submandibular glands in mice xenografted with prostate adenocarcinoma cells premedicated by atropine sublingually, at 15 mg kg⁻¹. The parotid glands are encircled in white, the submandibular glands are in orange, and the tumor is in red. (B) Normalized quantification of [⁶⁸Ga]Ga-PSMA-11 in the parotids, submandibular glands, and tumor in prostate-tumor-bearing mice. The red point represents the mean ± SEM; black points represent the sample dispersion.