An overactive serotonin pathway is frequent in many NETs, leading to the development of a tracer involved in the metabolism of serotonin.

The immediate serotonin precursor is 5-hydroxytryptophan (5HTP), which is decarboxylated to serotonin. Serotonin is further converted into 5-hydroxyin-doleacetic acid by monoamine oxidase and aldehyde dehydrogenase.

5HTP can be labeled with carbon-11 and has considerable potential for use in PET imaging, especially to study patients with midgut NETs. However, the production of ¹¹C-5HTP is a complex process and only a few centers are adequately equipped for it.

¹¹C-5HTP PET is reported to be superior to CT and SRS in NETs. In a study on 38 NET patients (including those with gastroenteropancreatic NETs and pulmonary NETs), lesions were detected in 95% of cases by ¹¹C-5HTP PET, in 84% by SRS and in 79% by CT [34].

Scanning is generally performed 20 minutes after the injection of ¹¹C-5HTP in patients orally pretreated with carbidopa, which is useful to optimize image quality. The interpretation of ¹¹C-5HTP PET images is facilitated by the high tumor-to-background ratio due to the low tracer concentration in normal tissues.

Iodine-123 was the first radiopharmaceutical to permit the visualization of neuroendocrine tumors [35]. Subsequently indium-111, linked to a somatostatin analog through the diethylenetriaminepentaacetic acid chelator (DTPA), was the first radiopharmaceutical to identify the same NETs through the receptor imaging mechanism.

A few years later ¹¹¹In-DTPA-pentetreotide obtained full approval of the regulatory authority and is commercially known as ¹¹¹In-Octreoscan.

Despite the development of numerous diagnostic radiopharmaceuticals with different somatostatin analogs, ¹¹¹In-Octreoscan is currently the only commercially available radiopharmaceutical and has significantly influenced the study of NETs.

Over the years, scan sensitivity has been incremented by using hybrid gamma cameras [36, 37], and is now substantially higher (75%) for pituitary gland tumors, GEP-NETs, paragangliomas, small cell lung cancer, and moderately high (40–75%) for insulinomas, pheochromocytomas and medullary thyroid carcinomas [36].

¹¹¹In-Octreoscan was also used as the first therapeutic radioreceptor agent because the peptide receptor complex is transported into tumor cells near the nucleus and its high-energy Auger electron conversion functions as a cytotoxic agent. In a multicenter study, 40 patients positive for somatostatin receptors who received at least 20 GBq of ¹¹¹In-Octreoscan showed some clinical benefit, but efficacy data were poor, with one partial remission, six minor responses and 14 cases of stable disease [38, 39].

The radiopharmaceutical is administered at a dosage of 185 MBq and the standard set of acquisitions includes static or total body images 4, 24 and 48 hours after injection. The long half-life of ¹¹¹In (T/2 2.8 days) makes it easier to assess the dynamics of the radiopharmaceutical uptake, which can sometimes be quite slow. After administration of the radiopharmaceutical, plasma clearance is fairly rapid and progressive tissue accumulation is seen. A normal scan shows physiological uptake in the spleen, kidneys and liver, while a variable uptake is present in the pituitary gland, thyroid, bladder and intestines. The images should be interpreted with the integration of clinical information and morphologic images. To define a region as hyperactive, its radiotracer concentration must be at least equal to that of the liver, and the intensity of radiopharmaceutical concentration is graded following a well-defined scale [40]. Uptake indices are also useful for providing indications for PRRT using either lutetium-177 or yttrium-90 DOTA-peptides.

¹¹¹In-Octreoscan false positive results may be linked to areas of inflammation or post-surgery scars. False negative results must also be evaluated for possible interference with cold somatostatin analog therapies.

The fundamental role played by ¹¹¹In-Octreoscan scintigraphy in the study of NETs prompted research into alternative PET radiopharmaceuticals that could take advantage of the superior technical characteristics of this type of imaging.

Various somatostatin analogs capable of binding with β⁺ emitter gallium-68 (t/2 68 minutes, 89% of positron emission with an energy of 830 keV) through the DOTA chelator were developed. Of these, octreotide (TOC) and octreotate (TATE), both endowed with high receptor affinity for SSTR2 and SSTR5, and [Nal3]-octreotide (NOC), with a high affinity for SSTR2, SSTR3 and SSTR5 [41], are the most widely used. In general, different receptor affinities of peptides did not result in a significant difference in sensitivity in their diagnostic use [9]. If anything, the difference is mainly linked to the fact the octreotide and octreotate, used in combination with β-emitting radionuclide yttrium-90 and lutetium-177, respectively, are widely employed in PRRT and therefore more suitable for theranostics (Fig. 8.1b,b1).

In recent years, there has been a substantial increase in publications on peptides labeled with ⁶⁸Ga-DOTA-peptides, but the most widely used are ⁶⁸Ga-DOTA-NOC and ⁶⁸Ga-DOTA-TOC, with a sensitivity of 90–98% and 92–98%, respectively [42]. Gallium-68 is obtained from the elution of a ⁶⁸Ge/⁶⁸Ga generator (most Nuclear Medicine Units have this equipment) and used to label a chosen peptide through the DOTA chelator.

The in-house availability of the radionuclide, together with its favorable diagnostic sensitivity, has largely contributed to the successful use of this β-emitter. Images are acquired about one hour after the administration of an average 100 MBq of gallium-68 (range 75–250 MBq). The physiological distribution of the radiopharmaceutical is found in the pituitary gland, spleen, liver, adrenals, head of the pancreas, thyroid, kidney and bladder. Although there are no proven indications for the suspension of an analogous cold therapy, it is advisable to perform the scan at least 20 days after the last injection. Asymmetrical areas of increased activity outside of normal distribution sites are classified as pathological. False positive images may be observed for accessory spleen, lymphoma and sites of inflammation. Uptake in the uncinate process of the head of the pancreas is not considered suspicious if the CT images are negative. In a series of 245 patients who underwent ⁶⁸Ga-DOTA-peptide PET, non-specific or diffuse uptake of the pancreatic head was found in 23% and 8% of patients, respectively. This phenomenon, if the SUV is comparable with that of the liver, can be considered non-specific [43].

Generally speaking, the significance of variations in SUV must be carefully evaluated because numerous parameters are involved in its definition and data may differ greatly from center to center [44].

An assessment of the sensitivity of ⁶⁸Ga-DOTA-peptide PET was made in 84 patients with NETs of various origin, comparing PET performance with that of CT and scintigraphy with ¹¹¹In-Octreoscan. PET showed higher sensitivity (97%) than CT (61%) or scintigraphy (52%) in evaluating lesions, especially in small tumors and lymph node and bone lesions [45, 46] (Fig. 8.1b1).

⁶⁸Ga-DOTA-peptide is indicated for well-differentiated NETs and is often capable of accurately identifying the unknown site of the primary tumor. At the same time, ⁶⁸Ga-DOTA-peptide offers the possibility of evaluating the extent of the disease [47] and provides indications for treatment with cold analogs or PRRT.

The indication for ⁶⁸Ga-DOTA-peptide PET is not limited to NETs as many tumors overexpress somatostatin receptors including medullary thyroid cancer, lymphoma, paraganglioma, glioblastoma, meningioma, breast cancer, sarcoma and Merkel-cell carcinoma. Consequently, patients with ⁶⁸Ga-DOTA-peptide PET-positive tumors, for whom there is often no effective therapy, may be candidates for PRRT.

Although the role of ⁶⁸Ga-DOTA-peptide PET in evaluating response to PRRT [47] has been acknowledged, there are still some concerns about the evidence that a potential dedifferentiation of the disease may generate false negative results.

Another interesting diagnostic option in this field is related to ¹⁷⁷Lu-DOTATATE PRRT. Lutetium-177 emits both β^– particles and gamma rays (208 KeV at 11% and 113 KeV at 6.5%). Imaging — generally achieved 24 hours after therapy — is of good quality and generally comparable to what can be achieved with ¹¹¹In-Octreoscan [48]. The administered activity is therapeutic and so fairly high (range 3.7/7.4 GBq each cycle) with respect to ¹¹¹In-Octreoscan (Fig. 8.2a,b). Consequently, images can be used to evaluate lesion uptake intensity, tumor burden, the presence of non-active lesions and possible tumor response or progression during cycles (Fig. 8.2b,c). This option also reduces the need to perform numerous morphological assessments between cycles.

Despite the success of PET with ⁶⁸Ga-DOTA-peptide, research has developed new important diagnostic possibilities using ⁶⁴Cu-DOTATATE. Thanks to the optimal physical characteristics of this radioisotope, which has a longer half-life than that of gallium-68 (t/2 12.7 hours, emission energy β⁺ 278 KeV), it is possible to acquire delayed images and to detect lesions with slow uptake, as in the case of ¹¹¹In-Octreoscan. In a recent study, 59 patients with NETs of various origin underwent PET with ⁶⁸Ga-DOTATATE and ⁶⁴Cu-DOTATATE. The latter agent detected 42 lesions not seen with ⁶⁸Ga-DOTATATE, 33 of which proved to be true positives during follow-up. Conversely, ⁶⁸Ga-DOTATATE highlighted 26 lesions not detected by PET ⁶⁴Cu-DOTATATE, but only seven of these were true positives [49].