Hyperparathyroidism is an increasingly significant medical and public health condition in the United States. In the past two decades, the incidence of hyperparathyroidism has increased 300%, and currently, the disease affects at least 30,000 new patients each year in the United States. Parathyroid adenomas, parathyroid hyperplasia in primary and secondary hyperparathyroidism, and parathyroid carcinomas all are increasing in frequency in this country. The causes of the increased incidence of hyperparathyroidism are not known. Multiple organs are affected in patients with hyperparathyroidism; notably, a worsening of the severity of osteoporosis an accelerated arteriosclerotic disease, and hypertension. Parathyroid carcinoma no longer is a rare illness and there is no effective oncologic therapy for parathyroid carcinoma (which often is fatal).

Surgery is the only effective management for primary hyperparathyroidism. Preoperative localization of a parathyroid adenoma allows a unilateral neck exploration for the removal of the tumor. If localization is accurate, patients can undergo focal, minimally invasive parathyroidectomies with cure rates equivalent to conventional surgery, less anesthesia, improved cosmesis, and shorter hospital stays. Since this approach decreases both the duration of surgery and its morbidity, preoperative localization is gaining recognition as an important procedure. However, tumor localization can be challenging, in part because current imaging methodologies are sub-optimal, failing to identify the parathyroid tumor in as many as 30% of patients. In re-operative parathyroidectomy for persistent or recurrent hyperparathyroidism, localization plays an even greater role.

Unfortunately, current imaging modalities fail to localize 10-15% of tumors. Even though high-frequency ultrasound can detect parathyroid adenoma, the intra-operator variability and difficulties in patients with prior surgery often necessitate Tc-99m MIBI imaging which has become the standard of care for preoperative localization which allows minimally invasive surgery and decreases the surgical time. The most commonly used methodology uses dual-phase 99mTechnetium-sestamibi (99mTc-MIBI) scintigrams where images are acquired at 2 and 4 hours after radiopharmaceutical administration. Interference caused by the concentration of 99mTc-MIBI in the thyroid (in close proximity of parathyroid adenoma) is a major source of failure of localization. Even if sophisticated techniques such as SPECT/CT are used, the parathyroid tumor is not identified in as many as 30% of patients. Parathyroid glands are located very close to the thyroid and if a molecular probe concentrates in the thyroid as well as in the parathyroid then the thyroid background makes it difficult to localize parathyroid adenomas. Our preliminary data has shown that folate receptors are not expressed in thyroid tissue and thus folate receptor imaging becomes an innovative technique of imaging parathyroid pathologies without the interference from the signals from the thyroid. This proposal is based on our observations that human parathyroid tumor cells express high densities of folate receptors and thyroid cells do not. Prostate-specific membrane antigen (PSMA) labeled with Ga-68 PSMA has been in clinical use in Europe and Asia for more than 5 years. The FDA approved the F 18-labeled prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging agent 18F-DCFPyL (Pylarify) for use in prostate cancer in May 2021. PSMA is also known as Glutamate carboxypeptidase II (GCP II), and N-acetyl-L-aspartyl-L-glutamate peptidase I (NAALADase I), NAAG peptidase. PSMA removes the g-linked glutamates from folate, providing deglutinated folate for absorption and nutrition and leaving single a-linked glutamate attached. The official gene name of PSMA is folate hydrolase 1 (FOLH1), reflecting its major role in folate uptake; however, PSMA usually acts as a glutamate carboxypeptidase (GCP), its major substrate can differ in different tissues. Yao et al. found that PSMA-expressing cells also demonstrated a 2-fold increased uptake of folate, suggesting that PSMA may be associated with folate transport. Ga-68 PSMA has been shown to concentrate in parathyroid adenoma and not in the thyroid (Pfob2019). Ga-68 has 68 minutes half-life, is generator produced, and is available for a few centers in California currently. F-18 PSMA had 120 minutes half-life and will be available as a unit dose. This makes F-18 PSMA an ideal agent for clinical use.

Researchers hypothesize that F-18 PSMA will give better pre-operative localization of parathyroid adenomas compared to the conventional imaging with 99mTc-MIBI. If this is the case the new method will provide more patients with a minimally invasive parathyroidectomy, reducing trauma to the patient and the healthcare costs. The project described here is designed to collect preliminary data for a larger study.