68Ge/68Ga radionuclide generators have been investigated for almost fifty years now, since the cyclotronindependent availability of positron emitting 68Ga via the 68Ge/68Ga system had always attracted researches working in basic nuclear chemistry as well as radiopharmaceutical chemistry. However, it took decades and generations of research (and researchers) to finally approach a reliable level of 68Ge/68Ga generator designs, adequate to the modern requirements of radiometal labeling chemistry. 68Ga radiopharmacy now is awaking from a sort of hibernation. The exciting perspective for the 68Ge/68Ga generator, now – more than ever, asks for systematic chemical, radiochemical, technological and radiopharmaceutical efforts, to guarantee reliable, highly-efficient and medically approved 68Ge/68Ga generator systems. The expected future broad clinical impact of 68Ga-labelled radiopharmaceuticals – beyond the 68Ga-DOTA-octreotide derivatives – for imaging tumors and many organs, on the other hand, identifies the development of sophisticated GaIII chelating structures to be a key factor. Today, open chain complexing agents have almost completely been displaced by macrocyclic DOTA and NOTA-derived conjugates. Structures of chelating moieties are being optimized in terms of thermodynamic stability and kinetic inertness, in terms of labeling efficacies at different, even acidic pH, and in terms of synthetic options towards bifunctionality, directed to sophisticated covalent coupling strategies to a variety of biologically relevant targeting vectors. Today, one may expect that the 68Ge/68Ga radionuclide generator systems could contribute to and facilitate the clinical impact of nuclear medicine diagnoses for PET in a dimension comparable to the established 99Mo/99mTc generator system for SPECT.

In the context of radiopharmacy and molecular imaging, the concept of theranostics entails a therapy-accompanying diagnosis with the aim of a patient-specific treatment. Using the adequate diagnostic radiopharmaceutical, the disease and the state of the disease are verified for an individual patient. The other way around, it verifies that the radiopharmaceutical in hand represents a target-specific and selective molecule: the “best one” for that individual patient. Transforming diagnostic imaging into quantitative dosimetric information, the optimum radioactivity (expressed in maximum radiation dose to the target tissue and tolerable dose to healthy organs) of the adequate radiotherapeutical is applied to that individual patient. This theranostic approach in nuclear medicine is traced back to the first use of the radionuclide pair ⁸⁶Y/⁹⁰Y, which allowed a combination of PET and internal radiotherapy. Whereas the β-emitting therapeutic radionuclide ⁹⁰Y (t½ = 2.7 d) had been available for a long time via the ⁹⁰Sr/⁹⁰Y generator system, the β⁺ emitter ⁸⁶Y (t½ = 14.7 h) had to be developed for medical application. A brief outline of the various aspects of radiochemical and nuclear development work (nuclear data, cyclotron irradiation, chemical processing, quality control, etc.) is given. In parallel, the paper discusses the methodology introduced to quantify molecular imaging of ⁸⁶Y-labelled compounds in terms of multiple and long-term PET recordings. It highlights the ultimate goal of radiotheranostics, namely to extract the radiation dose of the analogue ⁹⁰Y-labelled compound in terms of mGy or mSv per MBq ⁹⁰Y injected. Finally, the current and possible future development of theranostic approaches based on different PET and therapy nuclides is discussed.

Generator-derived radionuclides for PET/CT imaging are promising for optimizing targeted radiotherapy by an individual patient-based approach, applying pre-therapeutic evaluation, as well as dosimetric calculations, and for measuring treatment response after radionuclide therapy.

Recently, great interest has been gained regarding fibroblast activation protein (FAP) as an excellent target for theranostics. Several FAP inhibitor molecules such as [⁶⁸Ga]Ga-labelled FAPI-02, 04, 46, and DOTA.SA.FAPi have been introduced and are highly promising molecular targets from the imaging point of view. FAP inhibitors introduced via bifunctional DOTA and DOTAGA chelators offer the possibility to complex Lutetium-177 due to an additional coordination site, and are suitable for theranostic applications owing to the increased tumor accumulation and prolonged tumor retention time. However, for therapeutic applications, very little has been accomplished, mainly due to residence times of the compounds. In an attempt to develop a promising therapeutic radiopharmaceutical, the present study aimed to evaluate and compare the biodistribution, pharmacokinetics, and dosimetry of [¹⁷⁷Lu]Lu-DOTA.SA.FAPi, and [¹⁷⁷Lu]Lu-DOTAGA.(SA.FAPi)₂ in patients with various cancers. The FAPi agents, [¹⁷⁷Lu]Lu-DOTA.SA.FAPi and [¹⁷⁷Lu]Lu-DOTAGA.(SA.FAPi)₂, were administered in two different groups of patients. Three patients (mean age—50 years) were treated with a median cumulative activity of 2.96 GBq (IQR: 2.2–3 GBq) [¹⁷⁷Lu]Lu-DOTA.SA.FAPi and seven (mean age—51 years) were treated with 1.48 GBq (IQR: 0.6–1.5) of [¹⁷⁷Lu]Lu-DOTAGA.(SA.FAPi)₂. Patients in both the groups underwent serial imaging whole-body planar and SPECT/CT scans that were acquired between 1 h and 168 h post-injection (p.i.). The residence time and absorbed dose estimate in the source organs and tumor were calculated using OLINDA/EXM 2.2 software. Time versus activity graphs were plotted to determine the effective half-life (Te) in the whole body and lesions for both the radiotracers. Physiological uptake of [¹⁷⁷Lu]Lu-DOTA.SA.FAPi was observed in the kidneys, colon, pancreas, liver, gall bladder, oral mucosa, lacrimal glands, and urinary bladder contents. Physiological biodistribution of [¹⁷⁷Lu]Lu-DOTAGA.(SA.FAPi)₂ involved liver, gall bladder, colon, pancreas, kidneys, and urinary bladder contents, lacrimal glands, oral mucosa, and salivary glands. In the [¹⁷⁷Lu]Lu-DOTA.SA.FAPi group, the highest absorbed doses were noted in the kidneys (0.618 ± 0.015 Gy/GBq), followed by the colon (right colon: 0.472 Gy/GBq and left colon: 0.430 Gy/GBq). In the [¹⁷⁷Lu]Lu-DOTAGA.(SA.FAPi)₂ group, the colon received the highest absorbed dose (right colon: 1.160 Gy/GBq and left colon: 2.870 Gy/GBq), and demonstrated a significantly higher mean absorbed dose than [¹⁷⁷Lu]Lu-DOTA.SA.FAPi (p < 0.011). [¹⁷⁷Lu]Lu-DOTAGA.(SA.FAPi)₂ had significantly longer median whole-body Te compared to that of [¹⁷⁷Lu]Lu-DOTA.SA.FAPi [46.2 h (IQR: 38.5–70.1) vs. 23.1 h (IQR: 17.8–31.5); p-0.0167]. The Te of tumor lesions was significantly higher for [¹⁷⁷Lu]Lu-DOTAGA.(SA.FAPi)₂ compared to [¹⁷⁷Lu]Lu-DOTA.SA.FAPi [86.6 h (IQR: 34.3–94.6) vs. 14 h (IQR: 12.8–15.5); p-0.0004]. The median absorbed doses to the lesions were 0.603 (IQR: 0.230–1.810) Gy/GBq and 6.70 (IQR: 3.40–49) Gy/GBq dose per cycle in the [¹⁷⁷Lu]Lu-DOTA.SA.FAPi, and [¹⁷⁷Lu]Lu-DOTAGA.(SA.FAPi)₂ groups, respectively. The first clinical dosimetry study demonstrated significantly higher tumor absorbed doses with [¹⁷⁷Lu]Lu-DOTAGA.(SA.FAPi)₂ compared to [¹⁷⁷Lu]Lu-DOTA.SA.FAPi. [¹⁷⁷Lu]Lu-DOTAGA.(SA.FAPi)₂ is safe and unveiled new frontiers to treat various end-stage cancer patients with a theranostic approach.

44 Ti/ 44 Sc radionuclide generators are of interest for molecular imaging. The 3.97 h half-life of 44 Sc and its high positron branching of 94% may stimulate the application of 44 Sc labelled PET radiopharmaceuticals. However, both 44 Ti production and 44 Ti/ 44 Sc generator design represent challenges for basic radiochemistry. About 5 mCi (185 MBq) of 44 Ti were obtained via the Sc( p , 2 n ) nuclear reaction. 44 Ti was separated from 1.5 g of massive scandium targets in multi-step procedures, including exchange chromatography on cation exchange resin (AG 50W-X8, 200−400 mesh, H + -form). In order to design a robust 44 Ti/ 44 Sc generator concept, distribution coefficients of Ti(IV) and Sc(III) on both AG 1-X8 (200−400 mesh, Cl - -form) and AG 50W-X8 (200−400 mesh, H + -form) resins eluted with HCl and HCl/H 2 C 2 O 4 solution of various concentrations were investigated systematically. Optimal conditions for efficient separations of both radionuclides have been determined for AG 1-X8 resin and mixtures of 0.07 M HCl and 0.005 M H 2 C 2 O 4 . A 5 mCi generator was prepared on an AG 1-X8 column ( H =150 mm, D =3 mm, V 0 =0.55 mL). The system achieved elution of 180 MBq 44 Sc in 20 mL of eluate solution. The breakthrough of 44 Ti is 90 Bq. This corresponds to an excellent separation factor of 2×10 6 . In the context of long-term stability of 44 Ti/ 44 Sc generators, a “reverse” type of washing steps after each elution using 0.07 M HCl/0.005 M H 2 C 2 O 4 mixtures appeared to be essential.