[Note: This is an updated post from the original posted one year ago.]

March 22, 2022. Swiss drugmaker Novartis has released Pluvicto, “the first FDA-approved targeted radioligand therapy (RLT) for eligible patients with mCRPC that combines a targeting compound (ligand) with a therapeutic radioisotope (a radioactive particle). Pluvicto is expected to be available to physicians and patients within weeks.“

Pluvicto features a chelated ¹⁷⁷Lutetium ion (half-life 6.7 days) which is the source of the molecule’s radioactivity. Lutetium is the heaviest of the lanthanide elements and the name comes from the Latin Lutetia Parisiorum which was the predecessor to the city of Paris, France.

Pluvicto has been approved in the US for the treatment of metastatic prostate cancer. Several things are notable about the Pluvicto molecule. The molecule contains a PSMA-specific peptidomimetic feature with an attached therapeutic radionuclide, where PSMA stands for Prostate Specific Membrane Antigen. Peptidomimetic refers to a small chain that resembles a stretch of protein forming amino acids. This peptidomimetic fragment, which interestingly contains a urea linker, is designed as the tumor targeting piece of the drug. Connected to it is a chelated radioactive ¹⁷⁷Lutetium cation (below, upper right). The tumor targeting fragment binds to the cancer cell. While bound to the cell, the short-lived radioisotope undergoes two modes of decay. The ¹⁷⁷Lu has two decay modes. One emits a medium energy beta particle (E_βmax = 0.497 MeV) which is limited to a maximum of 0.670 millimeters of travel. This is the kill shot that will damage the attached and nearby target cells. The short path length of the beta ray in vivo limits the extent of surrounding damage by any given decay. Once the ¹⁷⁷Lu emits a beta particle it becomes ¹⁷⁷Hafnium.

The other mode of ¹⁷⁷Lu decay is gamma emission by ^177mLu, a nuclear isomer or metastable form of ¹⁷⁷Lu. Gamma radiation is much more penetrating than beta radiation. The gammas can be detected from the outside of the patient allowing monitoring of dose and location of the drug. Even though gamma rays are more penetrating than beta rays, they produce many fewer ion pairs per centimeter as they traverse the tissue making them less effective per photon in tissue destruction compared to alpha and beta particles. For instance, alpha particles from therapeutic radionuclides like ²²³Radium used to treat prostate cancer are much more destructive because they produce many ion pairs per centimeter.

A Small Side-Track into Radon Decay

Not all radioactive isotopes are alike. Some, like ¹⁷⁷Lu, offer only a single decay event while others are part of a domino series of decays. The decay of naturally occurring ²²²Radon begins a series of decay events (Radon’s daughters), with some decays being quite rapid, multiplying the radiological effect per initiating atom. Inhaling an alpha emitter like ²²²Radon is a gamble. Until the ²²²Rn decays, it is just an inert noble gas. But when it alpha decays in your lungs, it is converted to the ²¹⁸Polonium which alpha decays to ²¹⁴Lead which beta decays to ²¹⁴Bismuth which beta decays to ²¹⁴ Polonium which alpha decays to ²¹⁰Lead which beta decays to ²¹⁰Bismuth which beta decays to ²¹⁰Polonium which alpha decays to stable ²⁰⁶Lead where the chain stops. Each of the daughter products is a reactive, nonvolatile metal.

Neutron Activation of ¹⁷⁶Lutetium

How does one obtain ¹⁷⁷Lu? There are two pathways of nuclear chemistry that can be used, each with plus and minus attributes. The easiest pathway to execute would be the absorption of a thermal neutron by the lighter lutetium isotope ¹⁷⁶Lu followed by a gamma emission from the new ¹⁷⁷Lu. Gamma emissions result from metastable coproduct ^177mLu that is in an excited state. It can de-excite by losing the excited state energy by the release of a gamma photon.

An excellent review of this topic is by: Ashutosh, Dash; Maroor, Raghavan; Ambikalmajan, Pillai; and Furn F. Knapp, Jr. Nucl Med Mol Imaging. 2015 Jun; 49(2): 85–107. doi: 10.1007/s13139-014-0315-z.

Where does one get thermal neutrons and what is “thermal” about them? Thermal neutrons are produced in a water-cooled nuclear reactor. It turns out that nature has bestowed a wonderful gift on ¹⁷⁶Lu. It has a very large neutron capture cross section of 2090 barns for producing ¹⁷⁷Lu. The metastable ^177mLu isomer has a cross section of only 2.8 barns.

The unit “barn” is the unit of the effective target area of a nucleus and is equivalent to 10^-28 m², or 100 square femtometers. The capture cross section of a nucleus is dependent on the energy (or temperature) of a neutron and is proportional to the probability of a collision. Here is a brief reference on nuclear cross sections. The colorful etymology of the term “barn” is recalled here.

For comparison, the capture cross section of ²³⁹Plutonium is on the order of 750 barns with 0.025 electron volt neutrons. We can see that the capture cross section of the ¹⁷⁶Lu is much larger than that of ²³⁹Pu. The word “thermal” comes from the kinetic energy corresponding to the most probable speed of a free neutron at a temperature of 290 K (17 °C or 62 °F).

The transmutation [¹⁷⁶Lu + ⁰n —> ¹⁷⁷Lu + ^177mLu] is clean and direct with no other chemical elements to interfere. With its large capture cross section,¹⁷⁶Lu is well suited to absorb a neutron. The down side is that the isotopic abundance of ¹⁷⁶Lu is only 2.8 %. The other 97.2 % of Lu can also undergo neutron activation leading to chemical and radiological contamination of the desired ¹⁷⁷Lu. Isotopic separation of ¹⁷⁶Lu from the other Lu isotopes is difficult and not very scalable. By the way, the lutetium is neutron activated as the refractory oxide, Lu₂O₃. These lanthanide oxides are simple to prepare and can be dissolved in acid afterwards to produce Lu³⁺ cation for further chemistry.

Neutron Activation of ¹⁷⁶Ytterbium

The other major channel to ¹⁷⁷Lutetium is from neutron activation of ¹⁷⁶Ytterbium, ¹⁷⁶Yb. Generally speaking, the heavy lanthanides like Yb and Lu are less abundant than the light lanthanides on the left side of the series. All of the lanthanides have a 3+ oxidation state and similar ionic radii making them difficult to chemically separate, where “difficult” means that numerous steps are needed in purification often resulting in low yields. A few of the lanthanides have oxidation states other than +3. It turns out that Yb³⁺ can be selectively reduced by chemistry to Yb²⁺ in the presence of Lu³⁺ using sodium amalgam as the reductant. This happy fact allows for plausible chemical separation of Lu from Yb. Furthermore, Yb will amalgamate while Lu does not.

A Google search of Pluvicto or ¹⁷⁷Lutetium will produce many good links of a technical and non-technical nature.

Pluvicto, PSMA-targeted radiotherapy
(lutetium ¹⁷⁷Lu vipivotide tetraxetan)
for PSMA-positive prostate cancer
7.4 GBq (200 mCi) IV Q6W up to 6 doses