Positron Emission Tomography (PET) experienced accelerated development and has become an established method for medical research and clinical routine diagnostics on patient individualized basis. Development and availability of new radiopharmaceuticals specific for particular diseases is one of the driving forces of the expansion of clinical PET. The future development of the 68Ga-radiopharmaceuticals must be put in the context of several aspects such as role of PET in nuclear medicine, unmet medical needs, identification of new biomarkers, targets and corresponding ligands, production and availability of 68Ga, automation of the radiopharmaceutical production, progress of positron emission tomography technologies and image analysis methodologies for improved quantitation accuracy, PET radiopharmaceutical regulations as well as advances in radiopharmaceutical chemistry. The review presents the prospects of the 68Ga-based radiopharmaceutical development on the basis of the current status of these aspects as well as wide range and variety of imaging agents.

Abstract:The contribution of 68 Ga to the promotion and expansion of clinical research and routine positron emission tomography (PET) for earlier better diagnostics and individualized medicine is considerable. The potential applications of 68 Ga-comprising imaging agents include targeted, pre-targeted and non-targeted imaging. This review discusses the key aspects of the production of 68 Ga and 68 Ga-based radiopharmaceuticals in the light of the impact of regulatory requirements and endpoint pre-clinical and clinical applications.

Quantitative imaging and dosimetry are crucial for individualized treatment during peptide receptor radionuclide therapy (PRRT). 177 Lu-DOTATATE and 68 Ga-DOTATOC/ 68 Ga-DOTATATE are used, respectively, for PRRT and PET examinations targeting somatostatin receptors (SSTRs) in patients affected by neuroendocrine tumors. The aim of the study was to quantitatively and qualitatively compare the performance of 68 Ga-DOTATOC and 68 Ga-DOTATATE in the context of subsequent PRRT with 177 Lu-DOTATATE under standardized conditions in the same patient as well as to investigate the sufficiency of standardized uptake value (SUV) for estimation of SSTR expression. Methods: Ten patients with metastatic neuroendocrine tumors underwent one 45-min dynamic and 3 whole-body PET/CT examinations at 1, 2, and 3 h after injection with both tracers. The number of detected lesions, SUVs in lesions and normal tissue, total functional tumor volume, and SSTR volume (functional tumor volume multiplied by mean SUV) were investigated for each time point. Net uptake rate (K i ) was calculated according to the Patlak method for 3 tumors per patient. Results: There were no significant differences in lesion count, lesion SUV, K i , functional tumor volume, or SSTR volume between 68 Ga-DOTATOC and 68 Ga-DOTATATE at any time point. The detection rate was similar, although with differences for single lesions in occasional patients. For healthy organs, marginally higher uptake of 68 Ga-DOTATATE was observed in kidneys, bone marrow, and liver at 1 h. 68 Ga-DOTATOC uptake was higher in mediastinal blood pool at the 1-h time point (P 5 0.018). The tumor-toliver ratio was marginally higher for 68 Ga-DOTATOC at the 3-h time point (P 5 0.037). Blood clearance was fast and similar for both tracers. SUV did not correlate with K i linearly and achieved saturation for a K i of greater than 0.2 mL/cm 3 /min, corresponding to an SUV of more than 25. Conclusion: 68 Ga-DOTATOC and 68 Ga-DOTATATE are suited equally well for staging and patient selection for PRRT with 177 Lu-DOTATATE. However, the slight difference in the healthy organ distribution and excretion may render 68 Ga-DOTATATE preferable. SUV did not correlate linearly with K i and thus may not reflect the SSTR density accurately at its higher values, whereas K i might be the outcome measure of choice for quantification of SSTR density and assessment of treatment outcome.

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The glucagonlike peptide 1 receptor (GLP-1R) is mainly expressed on b-cells in the islets of Langerhans and is therefore an attractive target for imaging of the b-cell mass. In the present study, 68 Ga-labeled exendin-4 was evaluated for PET imaging and quantification of GLP-1R in the pancreas. Methods: Dose escalation studies of 68 Ga-labeled 1,4,7-tris(carboxymethylaza)cyclododecane-10-azaacetyl (DO3A)-exendin-4 were performed in rats (organ distribution) and cynomolgus monkeys (PET/CT imaging) to determine the GLP-1R-specific tissue uptake in vivo. Pancreatic uptake (as determined by organ distribution) in healthy rats was compared with that in diabetic rats. GLP-1R occupancy in the cynomolgus pancreas was quantified with a 1-tissue-compartment model. Results: In rodents, uptake in the pancreas was decreased from the baseline by up to 90% (P , 0.0001) by coadministration of DO3A-exendin-4 at 100 mg/kg. Pancreatic uptake in diabetic animals was decreased by more than 80% (P , 0.001) compared with that in healthy controls, as measured by organ distribution. GLP-1R occupancy in the cynomolgus pancreas after coinjection of DO3A-exendin-4 at 0.15-20 mg/kg ranged from 49% to 97%, as estimated by compartment modeling. Conclusion: These results strongly support the notion that 68 Ga-DO3A-exendin-4 uptake in the pancreas is mediated by specific receptor binding. In addition, pancreatic uptake was decreased by selective destruction of b-cells. This result suggests that GLP-1R can be quantified in vivo, which has major implications for the prospect of imaging of native b-cells.

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68 Ga-DOTATOC and 68 Ga-DOTATATE are 2 radiolabeled somatostatin analogs for in vivo diagnosis of neuroendocrine tumors with PET. The aim of the present work was to measure their comparative biodistribution and radiation dosimetry. Methods: Ten patients diagnosed with neuroendocrine tumors were included. Each patient underwent a 45-min dynamic and 3 whole-body PET/CT scans at 1, 2, and 3 h after injection of each tracer on consecutive days. Absorbed doses were calculated using OLINDA/EXM 1.1. Results: Data from 9 patients could be included in the analysis. Of the major organs, the highest uptake at 1, 2, and 3 h after injection was observed in the spleen, followed by kidneys and liver. For both tracers, the highest absorbed organ doses were seen in the spleen and urinary bladder wall, followed by kidney, adrenals, and liver. The absorbed doses to the liver and gallbladder wall were slightly but significantly higher for 68 Ga-DOTATATE. The total effective dose was 0.021 6 0.003 mSv/MBq for both tracers. Conclusion: The effective dose for a typical 100-MBq administration of 68 Ga-DOTATATE and 68 Ga-DOTATOC is 2.1 mSv for both tracers. Therefore, from a radiation dosimetry point of view, there is no preference for either tracer for PET/CT evaluation of somatostatin receptor-expressing tumors.

68 Ga-ABY-025 is a radiolabeled Affibody molecule for in vivo diagnosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer tumors with PET. The aim of the present work was to measure the biodistribution and estimate the radiation dosimetry of 68 Ga-ABY-025 for 2 different peptide mass doses in a single group of patients using dynamic and serial whole-body PET/CT. Methods: Eight patients with metastatic breast cancer were included. Each patient underwent an abdominal 45-min dynamic and 3 whole-body PET/CT scans at 1, 2, and 4 h after injection of a low peptide dose (LD) and a high peptide dose (HD), with approximately the same amount of radioactivity, in separate investigations 1 wk apart. As input to the absorbed dose calculations, volumes of interest were drawn on all clearly identifiable source organs: liver, kidneys, spleen, descending aorta, and upper large intestine. Absorbed doses were calculated using OLINDA/EXM, version 1.1. Results: Of the major organs, the highest radionuclide uptake at 1, 2, and 4 h after injection was observed in the kidneys and liver. The highest absorbed organ doses were seen in the kidneys, followed by the liver for both LD and HD 68 Ga-ABY-025. Absorbed doses to liver and kidneys were slightly but significantly higher for LD. Total effective dose was 0.030 ± 0.003 mSv/MBq for LD and 0.028 ± 0.002 mSv/MBq for HD. Conclusion: The effective dose for a typical 200-MBq administration of 68 Ga-ABY-025 is 6.0 mSv for LD and 5.6 mSv for HD. Therefore, from a radiation dosimetry point of view, HD is preferred for PET/CT evaluation of HER2-expressing breast cancer tumors. These effective doses are somewhat higher than earlier published values for other 68 Ga-labeled tracers, such as 0.021 ± 0.003 mSv/MBq for 68 Ga-DOTATATE and 68 Ga-DOTATOC, mainly because of higher uptake in liver and kidney. Forwomen,br east cancer is currently the most common cancer.Human epidermal growth factor receptor 2 (HER2) is overexpressed in about 1 of 6 cases (1-3) at initial diagnosis and is associated with poor survival (1,3). Treatments targeted to HER2, such as with the anti-HER2 antibody trastuzumab, have considerably improved overall survival (1,3,4). Today, assessment of HER2 status is based on tumor biopsy. However, HER2 expression can vary between the primary tumor and metastases in up to 40% of cases (2,5,6) and metastatic HER2 expression can change over time, which could necessitate a change of therapy (7,8). Follow-up using biopsies cannot always be performed due to practical reasons or patient discomfort.Molecular imaging using SPECT and PET might be a noninvasive, whole-body-based way to evaluate HER2 expression quantitatively. One such approach is the use of trastuzumab labeled with 111 In (half-time, 2.8 d) (9) or 89 Zr (3.3 d) (10) for use with SPECT and PET, respectively, but the slow kinetics of antibodies require imaging several days after administration. One promising method of fast, safe, and accurate imaging that specifically binds to a site on the receptor not occu...